Novel tricyclic compounds and drug compositions containing same

ABSTRACT

Compounds having a β-3 adrenaline receptor agonist and are useful as drugs for the treatment and prevention of diabetes, obesity, hyperlipemia, etc., represented by a general formula (I) and salts thereof, and a process for producing these, and their intermediates, wherein R represents hydrogen or methyl; R 1  represents hydrogen, halogen, hydroxy, benzyloxy, amino, or hydroxymethyl; R 2  represents hydrogen, hydroxymethyl, NHR 3 , SO 2 NR 4 R 4′ , or nitro; R 6  represents hydrogen or lower alkyl; and X represents nitrogen, R 9  represents hydrogen, one of R 7  and R 8  represent hydrogen, and the other thereof represents hydrogen, amino, acetylamino, or hydroxy.

FIELD OF THE INVENTION

[0001] The present invention relates to novel tricyclic compounds and todrug compositions containing such tricyclic compounds.

BACKGROUND OF THE INVENTION

[0002] In the past, it was accepted that β-adrenaline receptors areclassified into two groups β1 and β2, wherein the stimulation by inducesan increase in the cardiac rate and the stimulation by β2 brings aboutrelaxation in the smooth muscle tissue and lowering of blood pressure.Arch et al discovered a compound which exhibits scarce activities to β1and β2 but emphasizes lipolysis of fatty cells, wherefrom they have madeclear the existence of a third receptor [Nature, 309, 163-165 (1984)].Afterwards, the primary structure thereof was clarified [Emorine et al:Science, Vol. 245, 1118-1121 (1989)] and the receptor was named as β3.

[0003] Recently, it has been shown that compounds exhibiting aβ3-activity are useful as a drug for preventive treatment of diabetes,obesity, hyperlipemia, digestive diseases and depression [Int. J.Obesity 8 (suppl. 1), 93-102 (1984); Nature, 309, 163-165(1984); U.S.Pat. No. 5,120,766; Brit. J. Pharmacol., 103, 1351-1356 (1991); Eur. J.Pharmacol., 219, 193-201 (1992)].

[0004] Various compounds with correlation to β3 have been reported inthe literatures, for example, a compound (BRL 37344) having thefollowing molecular structure

[0005] as disclosed in EP 023 385 and in Drugs of the Future, Vol. 16797-800 (1991); a compound (CL316 243) having the following molecularstructure

[0006] as disclosed in EP 0 455 006 and J. Med. Chem., Vol. 35,3081-3084 (1992); a compound having the following molecular structure

[0007] as disclosed in WO₉₄₂₉₂₉₀; and a compound having the followingmolecular structure

[0008] as disclosed in EP 0 659 737 in Example 1 thereof. All thesecompounds have molecular structures different clearly from that of thecompound according to the present invention.

[0009] There was known a compound exhibiting a function for increasingthe myocardial contraction strength and for antagonizing obesityrepresented by the following structural formula

[0010] as disclosed in EP 171 702, which is distinguished from thecompound according to the present invention in that it has a strongpharmacological activity onto heart and has a molecular structure quitedifferent from that of the compound according to the present invention.

[0011] Further, a compound exhibiting an α, β-blocking activity, namely,a function of lowering the blood pressure, represented by the followingstructural formula

[0012] is disclosed in Japanese Patent Kokais Sho 55-53262 and Sho58-41860 and a compound exhibiting a vasodilatoric function representedby the following structural formula

[0013] is disclosed in DE 2 651 572. They are different from thecompound according to the present invention in the molecular structureand in the function.

[0014] There is a demand for a novel and effective medicament which canbe used for therapuetic treatment and preventive treatment of diseasescorrelating to β3, such as diabetes, obesity and hyperlipemia.

DISCLOSURE OF THE INVENTION

[0015] The inventors had been in sound researches for responding to theexisting demand by synthesizing various compounds and examining theirfunctions and reached the discovery that novel tricyclic compoundsrepresented by the general formula (I) given below had β3-activitieswith functions for lowering blood sugar value and for lipolysis, whichhas led to the completion of the present invention.

[0016] Thus, the present invention consists in a compound represented bythe general formula (I) or a salt thereof:

[0017] in which R represents hydrogen atom or methyl, R¹ stands forhydrogen atom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl,R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R⁴ or nitro,wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′), withR⁵ being a lower alkyl, benzyl or NR⁴R⁴ and R^(6′) being hydrogen atomor lower alkyl, and R⁵ and R^(4′) may be identical with or differentfrom each other and stand each for hydrogen atom, lower alkyl or benzyl,R⁶ represents hydrogen atom or lower alkyl, X stands for a secondarynitrogen atom, oxygen atom, sulfur atom or methylene and, in case X issecondary nitrogen atom, oxygen atom or sulfur atom, R⁹ stands forhydrogen atom and either one of R⁷ and R⁸ is hydrogen atom and the otherone is hydrogen atom, amino, acetylamino or hydroxy, or, in case X ismethylene, both R⁷ and R⁸ are hydrogen atom and R⁹ stands for hydrogenatom, amino, acetylamino or hydroxy,

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.

[0018] According to the present invention, there may be exemplified forthe halogen atom fluorine atom, chlorine atom, bromine atom or iodineatom, among them, fluorine atom and chlorine atom are preferred. In thecontext of the present invention, “lower alkyl” means a straight orbranched chain saturated hydrocarbon having 1-4 carbon atoms, such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl andt-butyl.

[0019] In the formula (I), R may preferably be hydrogen atom, while Rmay favorably be also methyl for reason of providing more higherselectivity.

[0020] R¹ stands for hydrogen atom, halogen atom, hydroxy, benzyloxy,amino or hydroxymethyl. A preferred example of the compound representedby the general formula (I) is one in which R¹ denotes hydrogen atom.Also preferred example of the compound represented by the generalformula (I) is one in which R¹ denotes amino or hydroxymethyl group. Afurther preferred example of the compound represented by the generalformula (I) is one in which R¹ denotes halogen atom or hydroxyl orbenzyloxy group.

[0021] R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R^(4′) ornitro. A preferred example of the compound represented by the generalformula (I) is one in which R² is hydrogen atom. Also preferred exampleof the compound represented by the general formula (I) is one in whichR² is hydroxymethyl or nitro group. A further preferred example of thecompound represented by the general formula (I) is one in which R²stands for NHR³ or SO₂NR⁴R′. R³ in the group NHR³ may be hydrogen atom,methyl, SO₂R⁵, formyl or CONHR^(6′), wherein preference is givenespecially to NHR³ which is NH₂, NHNe, NHSO₂R⁵ and NHCONHR^(6′), amongwhich NHSO₂R⁵ is more preferable. In the group NHSO₂R⁵, R⁵ stands forlower alkyl, benzyl or NR⁴R^(4′). R⁴ and R^(4′) may either be identicalwith or different from each other and may stand each for hydrogen atom,lower alkyl or benzyl, wherein either one of R⁴ and R^(4′) is preferablyhydrogen.

[0022] Concrete examples of NR⁴R^(4′) include amino, methylamino,ethylamino, propylamino, benzylamino, dimethylamino, diethylamino,dipropylamino, methylethylamino, methylpropylamino andmethylbenzylamino, among which preference is given to methylamino anddimethylamino. Therefore, preferred concrete examples of NHSO₂R⁴ includeNHSO₂Me, NHSO₂Et, NHSO₂CH₂Ph, NHSO₂NH₂, NHSO₂NHMe, NHSO₂NHEt, NHSO₂NMe₂,NHSO₂NEt₂, NHSO₂NMeEt and NHSO₂NMeCH₂Ph. R^(6′) in the groupNHCONHR^(6′) is hydrogen atom or lower alkyl. Concrete examples ofNHCONHR^(6′) include NHCONH₂, NHCONHMe, NHCONHEt and NHCONHPr.Concerning the group SONR⁴R^(4′) for the group R², the groups R⁴ andR^(4′) have the same meanings as given above and may either be identicalwith or different from each other and may stand each for hydrogen atom,lower alkyl or benzyl, wherein it is preferable that either one of R⁴and R^(4′) is hydrogen atom. Therefore, concrete examples of the groupSO₂NR⁴R^(4′) include SO₂NH₂, SO₂NHMe, SO₂NHEt, SO₂NMe₂, SO₂NEt₂,SO₂NHCH₂Ph and SO₂NMeCH₂Ph.

[0023] R⁶ represents hydrogen atom or lower alkyl. Preferred examplesinclude hydrogen atom, methyl and ethyl. Here, preference is given tothe case where it stands for hydrogen atom.

[0024] X stands for secondary nitrogen atom, oxygen atom, sulfur atom ormethylene. A preferred example of the compound is one in which X issecondary nitrogen atom, namely, the tricyclic skeleton is constitutedof carbazole group. Here, the groups R⁷, R⁸ and R⁹ have the meanings asgiven previously.

[0025] The symbol

1 in the general formula (I) indicates an asymmetric carbon atom and, incase R¹ is lower alkyl, the symbol

2 also indicates an asymmetric carbon atom. In this case, the compoundof the general formula (I) may be present in four isomers, namely,(R,R), (R,S), (S,S) and (S,R) represented by the sequence of (

1,

2). In case R⁶ is hydrogen atom, two isomers are possible. The presentinvention encompasses not only each optically pure isomer, but alsomixtures of two voluntarily selected isomer, of three voluntarilyselected isomers and of all four isomers. From the point of view ofdevelopment of the pharmacological activity, an asymmetric carbon atom (

1) in the ethanolamino chain may preferably have an absoluteconfiguration (R). Concerning the asymmetric carbon atom (

1) forN-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,especially preferred examples are R-hydroxy compounds.

[0026] For the compound according to the present invention, there arevery favorable groups of combinations of the substituent groups. In thefollowing, the symbols R⁶, X, R⁷, R⁸, R⁹,

1 and

2 for the general formula (I) have the meanings as defined above,so-long as no special mention is made.

[0027] When R² in the general formula (I) for the compound according tothe present invention represents hydroxymethyl, NHR³. SO₂NR⁴, R^(4′) ornitro, it is preferable that the group R¹ is in the 4- or 5-position,wherein preference is given to the case where R¹ is in 4-position. WhenR² is hydrogen atom, it is more preferable that R¹ is in the 2-position.

[0028] Preferred examples of the compound represented by the generalformula (I) or the salt thereof according to the present invention arethose in which the combination of the substituent groups in the generalformula (I) is such that “R represents hydrogen atom, R¹ stands forhydrogen atom, a halogen atom, hydroxy, benzyloxy, amino orhydroxymethyl and R² stands for hydrogen atom, hydroxymethyl, NHR³,SO₂NR⁴R^(4′) or nitro, wherein R³ is hydrogen atom, methyl, SO₂R⁵,formyl or CONHR^(6′), with R⁵ being lower alkyl, benzyl or NR⁴R^(4′) andR⁴ and R^(4′) may be identical with or different from each other andstand each for hydrogen atom, lower alkyl or benzyl and R^(6′) has themeaning as given above”.

[0029] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents hydrogen atom, R¹stands for hydrogen atom, fluorine atom, chlorine atom, hydroxy orbenzyloxy and R² stands for hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro,wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′) andeither one of R⁴ and R^(4′) is hydrogen atom and the other one ishydrogen atom, lower alkyl or benzyl, with R⁵ being lower alkyl, benzylor dimethylamino and R^(6′) being the same as given above”.

[0030] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents hydrogen atom, R¹stands for hydrogen atom, halogen atom, hydroxy or benzyloxy and R²stands for hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro, wherein R³ ishydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′), with R¹ being loweralkyl, benzyl or NR⁴R^(4′) and R¹ and R^(4′) may be identical with ordifferent from each other and stand each for hydrogen atom, a loweralkyl or benzyl and R^(6′) has the meaning as given above”.

[0031] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents hydrogen atom, R¹stands for hydrogen atom, fluorine atom, chlorine atom, hydroxy orbenzyloxy and R² stands for hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro,wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′) andeither one of R⁴ and R^(4′) is hydrogen atom and the other one ishydrogen atom, lower alkyl, benzyl, with R⁵ being a ;ower alkyl, benzylor dimethylamino and R^(6′) being the same as given above”.

[0032] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R and R¹ represent eachhydrogen and R² stands for hydroxymethyl, NHR³ or SO₂NR⁴R^(4′), whereinR³ is hydrogen atom, methyl, SO₂ ⁵, formyl or CONHR^(6′) with R¹ beinglower alkyl, benzyl or NR⁴R^(4′) and R⁴ and R^(4′) may be identical withor different from each other and stand each for hydrogen atom, loweralkyl or benzyl, and R^(6′) being the same as given above”.

[0033] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R and R¹ represent eachhydrogen atom and R² stands for hydroxymethyl, NHR³ or SO₂NR⁴R^(4′),wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′) andeither one of R⁴ and R^(4′) is hydrogen atom and the other one ishydrogen atom, lower alkyl or benzyl, with R⁵ being lower alkyl, benzylor dimethylamino and R^(6′) being the same as given above”.

[0034] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents hydrogen atom, R¹stands for halogen atom or hydroxy and R² stands for NHSO₂R⁵ orSO₂NR⁴NR^(4′), wherein R⁵ is lower alkyl, benzyl or NR⁴R^(4′) and R⁴ andR^(4′) may be identical with or different from each other and stand eachfor hydrogen atom, lower alkyl or benzyl”.

[0035] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents hydrogen atom, R¹stands for fluorine atom, chlorine atom or hydroxy and R² stands forNHSO₂R⁵ or SO₂R⁴R^(4′), wherein either one of R⁴ and R^(4′) is hydrogenatom and the other one is hydrogen atom, lower alkyl or benzyl and R⁵ islower alkyl, benzyl or dimethylamino”.

[0036] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R and R² represent eachhydrogen atom and R¹ stands for hydrogen atom, halogen atom or hydroxy”.

[0037] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R and R² represent eachhydrogen atom and R¹ stands for hydrogen atom, fluorine atom, chlorineatom or hydroxy”.

[0038] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents hydrogen atom, R¹stands for hydrogen atom, halogen atom, hydroxy, amino or hydroxymethyland R² stands for NHR³ or SO₂NR⁴R^(4′), wherein R³ is SO₂R⁵, with R⁵being lower alkyl, benzyl or NR⁴R^(4′), and R⁴ and R^(4′) may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl”.

[0039] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, halogen atom, hydroxy, benzyloxy, amino orhydroxymethyl and R² stands for hydrogen atom, hydroxymethyl, NHR³,SO₂NR⁴R^(4′) or nitro, wherein R³ is hydrogen atom, methyl, SO₂R⁵,formyl or CONHR^(6′), with R⁵ being lower alkyl, benzyl or NR⁴R^(4′),and R⁴ and R^(4′) may be identical with or different from each other andstand each for hydrogen atom, lower alkyl or benzyl and R^(6′) has themeaning as given above”.

[0040] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, fluorine atom, chlorine atom, hydroxy or benzyloxyand R² stands for hydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R^(4′) ornitro, wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′),with R¹ being lower alkyl, benzyl or NR⁴R^(4′), and either one of R⁴ andR^(4′) is hydrogen atom and the other one is hydrogen atom, lower alkylor benzyl and R^(6′) has the meaning as given above”.

[0041] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, halogen atom, hydroxy or benzyloxy and R² stands forhydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro, wherein R³ is hydrogen atom,methyl, SO₂R⁵, formyl or CONHR^(6′), with R⁵ being lower alkyl, benzylor NR⁴R^(4′), and R⁴ and R^(4′) may be identical with or different fromeach other and stand each for hydrogen atom, lower alkyl or benzyl andR^(6′) has the meaning as given above”.

[0042] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, fluorine atom, choline atom, hydroxy or benzyloxy andR² stands for hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro, wherein R³ ishydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′), with R⁵ being loweralkyl, benzyl or dimethylamino, and either one of R⁴ and R^(4′) ishydrogen atom and the other one is hydrogen atom, lower alkyl or benzyland R^(6′) has the meaning as given above”.

[0043] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom and R² stands for hydroxymethyl, NHR³, SO₂NR⁴R^(4′),wherein R³ is hydrogen atom, methyl, SO₂ ⁵, formyl or CONHR^(6′), withR⁵ being lower alkyl, benzyl or NR⁴R^(4′), and R⁴ and R^(4′) may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl and R^(5′) has the meaning as given above”.

[0044] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom and R² stands for hydroxymethyl, NHR³ or SO₂NR⁴R^(4′),wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′), withR⁵ being lower alkyl, benzyl or dimethylamino, and either one of R⁴ andR^(4′) is hydrogen atom and the other one is hydrogen atom, lower alkylor benzyl and R^(6′) has the meaning as given above”.

[0045] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor halogen atom or hydroxy and R² stands for NHSO₂R⁵ or SO₂NR⁴R^(4′),wherein R⁵ is lower alkyl, benzyl or NR⁴R^(4′), and R⁴ and R^(4′) may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl”.

[0046] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor fluorine atom, chlorine atom or hydroxy and R² stands for NHSO₂R⁵ orSO₂NR⁴R^(4′), wherein either one of R⁴ and R^(4′) is hydrogen atom andthe other one is hydrogen atom, lower alkyl or benzyl and R⁵ is loweralkyl, benzyl or dimethylamino”.

[0047] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, a halogen atom or hydroxy and R² stands for hydrogenatom”.

[0048] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, fluorine atom, chlorine atom or hydroxy, and R²stands for hydrogen atom”.

[0049] Also preferred examples of the compound represented by thegeneral formula (I) or the salt thereof according to the presentinvention are those in which the combination of the substituent groupsin the general formula (I) is such that “R represents methyl, R¹ standsfor hydrogen atom, halogen atom, hydroxy, amino or hydroxymethyl and R²stands for NHR^(6′) or SO₂NR⁴R^(4′), wherein R³ is SO₂R⁵, with R⁵ beinglower alkyl, benzyl or NR⁴R^(4′), and R⁴ and R^(4′) may be identicalwith or different from each other and stand each for hydrogen atom,lower alkyl or benzyl”.

[0050] Concrete examples of the compound represented by the generalformula (I) according to the present invention include

[0051](R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0052](S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0053]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0054]N-[5-[2-[2-(3-hydroxy-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0055]N-[5-[2-[2-(3-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl)-2-hydroxyphenyl]methanesulfonamide,

[0056]N-[5-[2-[2-(6-amino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0057]N-[5-[2-[2-(6-hydroxy-9H-carbazol-2-yloxy)ethylamino]-hydroxyethyl-2-hydroxyphenyl]methanesulfonamide,

[0058](R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-hydroxyethyl]phenyl]methanesulfonamide,

[0059](S)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethy]phenyl]methanesulfonamide,

[0060]N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0061]N-methyl-3-[2-[2-(9H-carbazol-2-Yloxy)ethylamino]-1-hydroxyethy]benzenesulfonamide,

[0062]N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide,

[0063](R)-N-[5-[2-[2-(dibenzofuran-3-Yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0064](S)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0065]N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0066]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]methanesulfonamide,

[0067]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chloropheny]methanesulfonamide,

[0068]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]1-2-fluorophenyl]methanesulfonamide,

[0069] N-[3-[2-[2-(dibenzofuran-3-yloxy)ethytamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0070]N-[5-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0071]N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0072]N-[3-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0073]N-[3-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0074]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]formamide,

[0075]N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamide,

[0076]N-[3-[2-[[-(9H-carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0077]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)ethanol,

[0078]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-amino-4-hydroxyphenyl)-ethanol,

[0079]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]urea,

[0080]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]urea,

[0081]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]formamide,

[0082]N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-dimethylsulfamide,

[0083]N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0084]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-(benzyloxy)phenyl]ethanol,

[0085]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-hydroxyphenyl]ethanol,

[0086] N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-2-propanesulfonamide,

[0087]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-nitrophenyl)ethanol,

[0088] N′-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethy,]phenyl]-N,N-dimethylsulfamide,

[0089]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-aminophenyl)ethanol.

[0090]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(hydroxymethyl)-4-hydroxyphenyl]ethanol,

[0091]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-hydroxyphenyl]methanesulfonamide,

[0092]N-(3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0093]N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamide,

[0094](R)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0095](S)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0096]N-[3-[2-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0097]N-[5-[2-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0098](R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

[0099](S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

[0100](R)-N-[5-[2-[2-(9H-carbazol-2-5yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

[0101](S)-N-(5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

[0102]N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide,

[0103]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamide,

[0104]N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamide,

[0105]N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamide,

[0106](R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfamide,

[0107](R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl)methanesulfonamide,

[0108](R)-N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0109]N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0110](R)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethytlamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0111](S)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0112]N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

[0113]N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

[0114]N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0115]N′-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0116]N-[3-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide,

[0117](R)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0118]N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamide,

[0119]N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamide,

[0120]N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0121]N′-(5-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide,

[0122]N′-[5-[2-(2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]-N-benzy>1-N-methylsulfamide,

[0123]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamide,

[0124]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxymethylphenyl]methanesulfonamide,

[0125]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide,

[0126]N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-benzyl-N-methylsulfamide,

[0127]N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamide,

[0128]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamide,

[0129]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamideand

[0130]N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamide.

[0131] The followings are concrete examples of the compound in whichboth R¹ and R² are hydrogen.

[0132]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyphenyl)ethanol,

[0133]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-fluorophenyl)ethanol,

[0134]2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanol,

[0135](R,R)-2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenyl]ethanol,

[0136] [2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0137] (R)-[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0138] (S)-[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0139][2-[N-[2-(3-acetylamino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0140][2-[N-[2-(3-amino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0141][2-[N-[2-(3-hydroxy-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol

[0142][2-[N-[2-(6-amino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0143][2-[N-[2-(6-acetylamino-9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanol,

[0144] [2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenyl]ethanoland

[0145] [2-[N-[2-(dibenzofuran-3-yloxy)ethyl]amino]-1-phenyl]ethanol.

[0146] Examples of the compounds in which R stands for methyl includethe followings.

[0147]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamide,

[0148]N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-methoxyethyl]-2hydroxyphenyl]methanesulfonamide,

[0149]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamideand

[0150]N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-chlorophenyl]methanesulfonamide.

[0151] The compound represented by the general formula (I) can beproduced, for example, by the following method.

[0152] <<Production process A>>

[0153] A compound represented by the general formula (II)

[0154] [in which R^(6′) represents hydrogen atom, halogen atom, aprotected hydroxyl group protected by a protecting group A, a protectedamino group protected by acetyl group or a protected hydroxymethyl groupprotected by acetyl group, R^(2′) stands for hydrogen atom, for aprotected hydroxymethyl group in which the hydroxyl group is protectedby a protecting group A′″, for NHR^(3′), for SO₂NR⁴R^(4′) or for nitro,wherein R^(3′) represents a protecting group for the amino group,methyl, SO₂R⁵, formyl or CONHR^(6′), with R⁵ being lower alkyl, benzylor NR⁴R^(4′) and R^(6′) being hydrogen atom or lower alkyl, R⁴ andR^(4′) may be identical with or different from each other and stand eachfor hydrogen atom, lower alky or benzyl, R⁵ denotes hydrogen atom orloser alkyl, A′ represents a protecting group for the hydroxyl group, Bis bromine atom or iodine atom and

1 indicates an asymmetric carbon atom] is reacted with a compoundrepresented by the general formula (III)

[0155] [Wherein Y represents hydrogen atom, R⁶ is hydrogen atom or loweralkyl, X is secondary nitrogen atom, oxygen atom, sulfur atom ormethylene and, in case X is secondary nitrogen atom, oxygen atom orsulfur atom. R^(9′) is hydrogen atom and either one of R^(7′) and R^(8′)is hydrogen atom and the other one is hydrogen atom, acetylamino or aprotected hydroxyl group protected by a protecting group A″, or, in casethat X is methylene, both R^(7′) and R^(8′) are hydrogen atom and R^(5′)stands for hydrogen atom, acetylamino or a protected hydroxyl groupprotected by a protecting group A′, and

2 indicates asymmetric carbon atom, when R⁶ is lower alkyl], and theprotecting groups A (proviso that in case that R¹ is benzyloxy and theprotecting group A is Benzyl, the protecting group A is notdeprotected), A′, A″, A′″ and the protecting group for amino group inR^(3′) (proviso that if is exists), or the protecting acetyl group inR^(1′) are deprotected to obtain the compound represented by the generalformula (I), [wherein R represents hydrogen atom, R¹ stands for hydrogenatom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R²stands for hydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro,proviso that R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′),and R⁵ is lower alkyl, benzyl or NR⁴R^(4′) and R⁴ and R^(4′) may beidentical with or different from each other and are hydrogen atom, loweralkyl or benzyl group. R^(6′) is represents hydrogen atom or loweralkyl.

[0156] As the protecting groups for protecting the hydroxyl groups,there is no special limitation so long as ordinary use is permitted andthere may usually be used as a protecting group which can be deprotectedeasily and selectively, for example, benzyl or t-butyl-dimethylsilyl forthe protecting group A, triethylsilyl for the protecting groups A′ andA′″ and methyl or benzyl for the protecting group A″. For introducing aprotecting group into the compound to be protected, known practice isemployed and, for example, a method is used for protecting the compoundby introducing therein benzyl group, in which the compound is reactedwith 1.1 molar times benzyl bromide at room temperature in a reactionsolvent, such as dimethylformamide, in the presence of potassiumcarbonate. For protecting the compound by introducing thereintriethylsilyl group, the compound is reacted with 1.2-2 molar timessilylating agent, such as triethylsilyl chloride, at a temperature inthe range of 0 to 30° C. in a reaction solvent, such as pyridine, for1-3 hours.

[0157] As the protecting group for protecting the amino group in thesubstituent R^(3′), there is no special limitation so long as ordinaryuse as a protecting group for protecting aniline is permitted and acetylgroup may usually be preferred therefor. For practising the acetylation,a reaction with acetic anhydride in a reaction solvent, such aspyridine, may be exemplified.

[0158] The coupling reaction of the compound represented by the generalformula (II) with the amine represented by the general formula (III) maybe realized using 1 to 1,5 moles of the amine of the general formula(III) per 1 mole of the halide of the general formula (II) in a polarsolvent, such as dimethylformamide, dimethylacetamide ordimethylsulfoxide, in the presence of a proton capturing agent, forexample, an amine, such as triethylamine or diisopropylethylamine, at atemperature in the range from room temperature to 90° C., preferably byheating at 60° C. for 5-10 hours.

[0159] Deprotection, of the resulting product may be effected either insuccession or simultaneously, While deprotection in a successive orderof A′, A″ A′″ the protecting agent for the amino group in R^(3 ′) and atlast A may be preferred. The deprotection of benzyl group for A and A″is realized bat hydrogenolysis in a solvent, such as methanol, using acatalyst, such as palladium or nickel. In the case where the substituentR¹ in the general formula (I) is benzyloxy, there is no need ofelimination of benzyl group as the protecting group A. The deprotectionof benzyl or methyl as the protecting groups A and A″ may be realized bytreating the product with a Lewis acid, such as boron tribromide, in asolvent, such as methylene chloride. The deprotection ofacetyl-protected hydroxyl group in the substituent R^(1′) may berealized by a known procedure of hydrolysis of ester. Concretely, it maybe performed in an alcohol using an alkali at room temperature or byheating under reflux of the solvent. The deprotection of triethylsilylas the protecting group A′ or A′″ may be realized by treating theproduct by adding thereto acetic acid and 3-5 molar timestetrabutylammonium fluoride in a solvent of tetrahydrofuran at roomtemperature for 30-5 hours. The deprotection of the protecting group,such as acetyl, for the amino group in R^(3′) or of the acetyl-protectedamino group in R^(1′) may be realized either by treating the productsmith hydrochloric acid at room temperature or by heating in a solvent,such as water or methanol, with an alkali.

[0160] The compound represented by the general formula(II) can beobtained by subjecting a compound represented by the following generalformula (V),

[0161] in which R^(1′) and R^(2′) have the same meanings as givenpreviously, to a reduction in the manner as described below, andreplacing the bromide, if the contemplated substituent group B in thegeneral formula (II) is iodine, iodide, followed by protection of thehydroxyl group.

[0162] The reduction of the compound represented by the general formula(V) may, be attained by using a reducing agent, such as a borane, whenthe steric configuration (

1) of the hydroxyl group of the compound represented by the generalformula (II) is racemic.

[0163] In case where either R- or S-optical isomer is to be obtained asto the

1 structure in the general formula (II), the reduction can be attainedby having resort to employment of a chiral assistant, such as given bythe following general formula (VI).

[0164] Thus, the reduction of the compound represented by the generalformula (V) is effected using a borane in the presence of theabove-mentioned chiral assistant. The reduction may preferably beperformed in a solvent, such as tetrahydrofuran. The preparation of sucha chiral assistant and the reaction therewith may be carried out inaccordance with the teachings in the literature [E. J. Corey et al, J.Org. Chem., Vol. 56, 442, (1991)].

[0165] After the reduction of the compound represented by the generalformula (V), the bromide thereof is, if necessary, replaced with iodideby, for example, treating the reduced compound with 3-10 times molaramount of an iodizing agent, such as sodium iodide, in a solvent, suchas acetone, with heating under reflux for 1-3 hours.

[0166] The hydroxyl group of the so-treated product is then protected bythe method described previously with a protecting group, such astriethylsilyl, to obtain the compound represented by the formula (II).

[0167] The compound represented by the general formula (V) is known andcan be synthesized by methods given in literatures, for example, A. A.Larsen et al, J. Med. Chem., 10, 462 (1967): or C. Kaiser et al, J. Med.Chem. 17, 49 (1974).

[0168] The compound represented by the general formula (III) can beobtained by reacting a compound represented by the general formula (VII)

[0169] in which Y denotes a protecting group for the amino group, R^(1′)and

2 have the same meanings as those given previously, with a compoundrepresented by the general formula (VIII)

[0170] in which X, R^(7′), R^(8′) and R^(9′) have the same meanings asthose given previously. As the protecting group Y for protecting theamino group, there is no special limitation so long as a usual use ispermitted and there may be exemplified one which can usually bedeprotected easily, for example, benzyloxycarbonyl, a substitutedbenzyloxycarbonyl, t-butoxycarbonyl, acetyl or trifluoroacetyl.

[0171] The reaction of the compound represented by the general formula(VII) with the compound represented by the general formula (VIII) can berealized, for example, in an organic solvent usually in the presence ofa base at a temperature from room temperature to the reflux temperatureof the solvent employed. As the solvent, there may be employed, forexample, dimethylformamide, dimethylacetamide, acetonitrile, diglym andtetrahydrofuran. As the base, there may be employed, for example,potassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, triethylamine, pyridine, sodium hydride or sodium methoxide,in an amount of, preferably, 1-10 moles per one mole of the compound ofthe general formula (VII).

[0172] The compound represented by the general formula (III) can, inparticular, if the above reaction does not proceed promptly, also besynthesized in accordance with the process described in Bull. Chem. Soc.Japan, 55, 2504 (1982) or by an improvement thereof. For example, onemole of the alcohol compound is reacted with 2-5 moles of the compoundrepresented by the general formula (VII) in a solvent, such asdimethylformamide or acetonitrile, in the presence of 5-10 moles of 40%potassium fluoridealumina at a temperature in the range from roomtemperature to 90° C. In the improved process, the above reaction isrealized with addition of 0.1-0.5 equivalent of potassium iodide.

[0173] Then, the protecting group Y for protecting the amino group isdeprotected to obtain the amine compound represented by the generalformula (III) wherein Y stands for hydrogen atom. The deprotection maybe effected by a usual method, for example, by a hydrogenolysis in asolvent, such as methanol, using a catalyst, such as palladium/carbonblack or by treating with hydrogen bromide/acetic acid. If theprotecting group Y is acetyl or trifluoroacetyl, the deprotection may beattained by treating with an alkali in a solvent, such as methanol, toobtain the compound represented by the general formula (III) in which Ydenotes hydrogen atom.

[0174] The compound represented by the general formula(VII) can besynthesized from a commercial product of an amino alcohol having thesubstituent R⁶ and a stereo structure of

2 by first protecting the amino group thereof with a protecting group Yand, then, the resulting product is subjected to bromination by a usualmethod. If there is an easily available aminobromo compound, thecontemplated compound can be obtained by merely protecting the aminogroup by a protecting group Y. For example, a hydrobromide salt of acommercial 2-bromoethylamine may be reacted with benzyloxycarbonylchloride in a solvent, such as methylene chloride, in the presenceof-triethylamine under cooling with ice water.

[0175] The compound represented by the general formula (VIII) in which Xstands for secondary nitrogen atom, oxygen atom or sulfur atom and thatin which X stands for methylene can be produced by the methods givenbelow, respectively.

[0176] The compound of the general formula (VIII) in which X issecondary nitrogen atom, oxygen atom or sulfur atom, both R^(8′) andR^(9′) are hydrogen atom and R^(7′) is hydrogen atom, acetylamino or aprotected hydroxyl group protected by a protecting group A′ can beproduced in a manner as follows:

[0177] Thus, starting from a commercial product of 2-hydroxycarbazoleand 3-methoxydibenzofuran or 3-hydroxydibenzothiophene which can besynthesized by method given in literature [H. Kudo et al, J. Heterocycl.Chem., 22(1), 215-218 (1985)] the compound represented by the formula(VIII) is obtained. The compound of the general formula (VIII) in whichR^(7′) is a substituent group other than hydrogen atom can be obtainedby, for example, in such a manner that the hydroxyl group of acommercial product of 2-hydroxycarbazole is protected by benzylating it,then, nitration is effected to introduce nitro group at the position ofthe substituent group R^(7′) and this is reduced into amino group,whereupon this amino group is acetylated or is subjected todiazotization with subsequent conversion into hydroxyl group, followedby protection of the resulting hydroxyl group by a protecting group A″and subsequent deprotection of the benzyl group to build up the compoundof the general formula (VIII).

[0178] For the nitration, ordinary methods given in the literatures maybe employed, wherein, for example, the benzyl-protected product issubjected to nitrationin acetic acid using an equivalent amount ofdiluted fuming nitric acid at a temperature of from room temperature to60° C. Reduction of the resulting nitro group may be effected by ausually employed method, for example, by hydrogenation in a solvent,such as methanol, in the presence of a catalyst, such as palladium oxideat room temperature or by using hydrochloric acid with iron powder or inthe presence of divalent tin at a temperature in the range from roomtemperature to the reflux temperature. The resulting amine may beacetylated using acetylchloride in a solvent. such as methylenechloride, at a temperature of from 0° C. to room temperature or may beconverted into hydroxyl group by first diazotizing it using, forexamples sodium nitrite, and, then, subjecting the resulting diazoniumsalt to a thermal decomposition in an acidic aqueous solution, followedby protection of the resulting hydroxyl group with a protecting group A″by the technique for protecting hydroxyl group described previously and,finally, deprotecting the benzyl group.

[0179] The compound of the general formula (VIII) in which X issecondary nitrogen atom, oxygen atom or sulfur atom, both R^(7′) andR^(9′) are hydrogen atom and R^(8′) is hydrogen atom, acetylamino or aprotected hydroxyl group protected by a protecting group A″ can beproduced in the manner as follows:

[0180] Thus, it can be synthesized starting from a known compound, i.e.2-acetylcarbazole represented by the general formula (IX)

[0181] in which X is secondary nitrogen atom, oxygen atom or sulfur atom[J. B. Kyziol et al, Tetrahedron, 36, 3017-3019 (1980)],3-acetyldibenzofuran [M. I. Shevchuk et al, Zh. Obshch. Khim., 40 (8),1717-1725 (1970)] or 3-acetyldibenzothiophene [Phosphorus, SulfurSilicon Relat. Elem., 72(1-4), 13-31 (1992); E. Camagine et al. J.Heterocycl. Chem. 6 (4), 517-522 (1969)]. For the compound in whichR^(8′) is a substituent group other than hydrogen atom, it may beprocessed, for example, by nitrating 2-acetylcarbazole at its positionof the substituent group R^(8′), followed by reduction of the resultingnitro group into amino group, whereupon the amino group is subjected toeither acetylation or diazotization with subsequent conversion intohydroxyl group, which is then protected by a protecting group A″ forprotecting hydroxyl group.

[0182] For example, for producing the compound represented by thegeneral formula (VIII) from the so-obtained acetyl group-containingcompound, namely, for converting the acetyl group into hydroxyl group,the acetyl group at the 2-position of carbazole is oxidized by a peracidinto acetyloxy which is, then, subjected to hydrolysis. Other processsteps than the oxidation of the acetyl group and the hydrolysis may beaccomplished in the same manner as in the case of introduction of R^(7′)described above. The oxidation by a peracid can be realized using, forexample, m-chloro-perbenzoic acid and disodium hydrogenphosphate in asolvent, such as methylene chloride, at room temperature and thehydrolysis can be realized by, for example, using sodium hydroxide in amixed solvent of water/ethanol.

[0183] The compound represented by the general formula (VIII) in which Xis methylene (fluorene), both R^(7′) and R^(8′) are hydrogen atom andR^(9′) is hydrogen atom or acetylamino is known and a commercial productthereof is available from, for example, the firm Sailor. In the casewhere R^(9′) is a protected hydroxyl group protected by a protectinggroup A″, the compound can be produced by protecting the hydroxyl groupof fluorene with benzyl group, de-protecting the acetyl group in theacetylamino group, diazotizing the resulting amino group, converting itinto hydroxyl group via a diazonium salt, protecting the resultinghydroxyl group by a protecting group A″ for protecting hydroxyl groupand finally de-protecting the benzyl group. These reaction series can beperformed by the method described previously.

[0184] Alternatively, for producing the compound of the general formula(III) in which either one of R^(7′), R^(8′) and R^(9′), is a protectedhydroxyl up protected by a protecting group A″, methods as given belowmay be incorporated.

[0185] Thus, the compound represented by the general formula (III) inwhich Y denotes a protecting group for protecting amino group, R^(7′),R^(8′) and R^(9′) denote each acetyl group in accordance with X and R⁶and

2 have the same meanings as those given previously is subjected tohydrolysis of the acetylamino group thereof into amino group. Theresulting amino group is diazotized and converted into hydroxyl group,which is then protected by a protecting group A′, whereupon theprotecting group Y of the amino group is deprotected to obtain thecompound represented by the general formula (III) in which Y is hydrogenatom.

[0186] As a further alternative method, the compound represented by thegeneral formula (I) in which R is hydrogen atom can be obtained using acompound represented by the general formula (IV)

[0187] in which Y′ is hydrogen atom or a protecting group for aminogroup and R^(1′), A′, R⁶, X, R^(7′), R^(8′), R^(9′),

1 and

2 have the same meanings as those given previously, as an importantsynthesis intermediate.

[0188] For producing the compound represented by the general formula(IV), the compound represented by the general formula (II) in whichR^(2′) is nitro and the compound represented by the general formula(III) in which Y stands for hydrogen atom are brought into couplingreaction and, if necessary, the amino group of the reaction product isprotected. The protecting group for the amino group in the substituentgroup Y′ of the general formula (IV) may be the same as that for theamino group in the substituent group Y explained above and theintroduction and elimination thereof may also be effected in the samemanner.

[0189] For producing the compound represented by the general formula (I)using the compound represented by the general formula (IV) as asynthesis intermediate, the following techniques may be exemplified:

[0190] Thus, the compound represented by the general formula (IV) isfirst reduced, namely, the nitro group thereof is reduced, to obtain acompound represented by the general formula (X)

[0191] in which Y′ is a protecting group for the amino group and R^(1′),A′, R⁶, X, R^(7′), R^(8′), R^(9′),

1 and

2 have the same meanings as those given previously.

[0192] For the above-mentioned reduction, the amino group of thecompound of the general formula (IV) may preferably have been protectedby the protecting group Y′ and the reduction may be performed by, forexample, hydrogenating the compound in a solvent, such as methanol, inthe presence of a catalyst, such as palladium oxide, or by using asystem employing hydrochloric acid with iron powder or a divalent tin.

[0193] Thereafter, the resulting product is subjected to formulation,sulfonation or urearization of amine (aniline) in accordance with therequirement for providing various substituent groups for R³ by, forexample, a method described in the literature, C. Kraiser et al, J. Med.Chem., 17, 49 (1974), to convert it into a compound represented bad thegeneral formula(XI)

[0194] in which Y′, R^(1′), A′, R³, R⁶, X, R^(7′), R^(8′), R^(9′),

1 and

2 have the same meanings as those given previously, whereupon theexisting protecting groups among A, A′, A′″ and that for the amino groupin Y′ are de-protected by the method for deprotection describedpreviously, to produce the compound represented by the generalformula(I) in which R is hydrogen atom.

[0195] The formylation mentioned above may be effected by, for example,heating the resulting product of the general formula (X) in ethylformate or by reacting it with a mixture of formic acid/acetic anhydrideat a temperature of from cooling with ice water to room temperature. Theabove mentioned sulfonation may be effected by, for example, reactingthe resulting compound of the general formula (X) with a sulfonylchloride substituted by a group R⁵ in a solvent, such as pyridine, at atemperature of from cooling with ice water to room temperature. Theurearization mentioned above can be attained by, for example, reactingthe resulting compound of the general formula (X) with sodium cyanate(NaOCN) at room temperature or under heating at, for example, 60° C. ina mixed solvent of water/acetic acid.

[0196] Alternatively, there is a method in which a racemic compound isobtained by a brief process step using, in the place of the compound ofthe general formula (II), the compound represented by the generalformula (V)

[0197] in which R^(6′) and R^(2′) have the same meanings as givenpreviously.

[0198] Thus, the compound represented by the above general formula (V)is reacted with the compound represented by the general formula (III) inwhich Y is hydrogen atom and the resulting ketoamine compound is, then,reduced, whereupon the protecting groups A, A″, A′″ and that forprotecting the amino group in the group R^(3′) are de-protected, withthe proviso that the deprotection of the protecting group A isunnecessary for the case where R¹ stands for benzyloxy and theprotecting group A is benzyl, whereby the compound represented by thegeneral formula (I) in which R is hydrogen atom and R¹, R², R⁶, X, R⁷,R⁸, R⁹,

1 and

2 have the same meanings as those given previously is obtained.

[0199] The reaction of the compound of the general formula (V) with thecompound of the general formula (III) can be attained by the methoddisclosed in the literature, A. A. Larsen et al, J. Med. Chem. 10, 462(1967), with an improvement in such a manner that the reaction iseffected in a polar solvent, such as acetonitrile, dimethylformamide,dimethylacetamide or dimethylsulfoxide, in the presence or absence of anamine as the acid-capturing agent under cooling with ice water or withheating at a temperature up to 60° C., followed by reduction of thecarbonyl group using a reducing agent, such as sodium borohydride orsodium cyanoborohydride, under cooling with ice water or at roomtemperature, followed by deprotection of the protecting group. By thisreaction, a racemic mixture of

1 is obtained, so that an optical resolution by the method as givenafterwards becomes necessary for obtaining each optical active compound.

[0200] <<Production Process B>>

[0201] As an alternative production process in which each optical activecompound or racemic modification is obtained, a technique using anepoxide may be incorporated.

[0202] Thus, the compound represented by the general formula (I) inwhich R is hydrogen atom and R¹, R², R⁶, X, R^(7′), R^(8′), R^(9′),

1 and

2 have the same meanings as those given previously can be produced byreacting a compound represented by the general formula (XII),

[0203] in which R′, R^(2′) and

1 have the meanings as those given previously, with the compoundrepresented by the general formula (III) in which Y denotes hydrogenatom and X, R⁶, R^(7′), R^(8′), R^(9′) and

2 have the same meanings as those defined previously, followed bydeprotection of the pretecting groups A, A″, A′″, that for protectingthe amino group in the substituent R³ and the protecting acetyl groupfor R^(1′) by the method described in the paragraph “Production ProcessA”, with the proviso that the deprotection of the protecting group A isunnecessary when R¹ is benzyloxy and the protecting group A is benzyl.

[0204] The reaction of the compound represented by the general formula(XII) with the compound represented by the general formula (III) can becarried out in a usual organic solvent, for example, dimethylsulfoxide,a straight chained or cyclic ether, dimethylformamide ordimethylacetamide. While the compound represented by the general formula(XII) and that represented by the general formula (III) are used oftenin an equimolar proportion, it is preferable to use an excess of thecompound represented by the general formula (III) over the compound ofthe general formula (XII). The reaction is effected at an adequatetemperature and, usually, at room temperature or the reflux temperatureof the solvent employed. The reaction duration may be selected inaccordance with the reaction condition and other factors and, usually,the reaction can be terminated at the point at which the yield becomesmaximum.

[0205] It was reported that the yield of the reaction can be increasedand the reaction duration is reduced by adding to the reaction mixturetrimethylsilylacetamide (TMSA) [N,O-bis(trimethylsilylacetamide)],hexamethyldisilazane (HMDS) or bis(trimethylsilyl)urea [TetrahedronLetters, 27, 2451 (1986)] and this may adequately be incorporatedherein.

[0206] The compound represented by the general formula(XII) is known andcan be synthesized by an ordinary method given in chemical literatures.For example, the general formula (XII) can be produced by oxidizingstyrene or a substituted styrene derivative using a peracid, such asm-chloroperbenzoic acid, or by reacting dimethylsulfonium methylideordimethylsulfoxonium methylide with a substituted benzaldehyde having asubstituent group corresponding to R^(1′) or R^(2′), as described in J.Am. Chem. Soc., 87, 1353 (1956).

[0207] An optical active compound represented by the general formula(XII) can be produced by reducing the compound represented by thegeneral formula (II) or a substituted mandelic acid derivative in whichthe α-carbon atom (

1) is in a desired absolute configuration into a corresponding glycolderivative, tosylating or mesylating or halogenating, then, theresulting primary alcohol and cyclizing the resulting compound using astrong base, such as an alkali metal hydroxide, under a usualintramolecular nucleophilic substitution reaction.

[0208] <<Production Process C>>

[0209] Alternatively further, there is a method for producing a racemicmodification by condensing a phenylglyoxal compound represented by thegeneral formula (XIII)

[0210] in which R^(1′) and R^(2′) have the same meanings as those givenpreviously with an amine compound represented by the general formula(III) in which Y is hydrogen atom and X, R⁶, R^(7′), R^(8′), R^(9′) and

2 have the same meanings as those given previously and reducing theresulting compound, with final deprotection of the protecting groups A,A″, A′″, the protecting group for the amino group of R³′ and theprotecting acetyl group of R¹′ by the procedure described in theparagraph of “Production Process A”, with the proviso that thedeprotection of the protecting group A is unnecessary when R¹ isbenzyloxy and the protecting group A is benzyl.

[0211] This reaction is carried out in general in a reaction solvent byreducing the Schiff base resulting from the condensation reaction usingan adequate reducing agent capable of reducing the Schiff base and atthe same time reducing the oxo-group-into hydroxyl group. As thereducing agent, there may be employed, for example, sodium borohydride,sodium cyanoborohydride and lithium cyanoborohydride. The proportion ofthe phenylglyoxal compound to the amine compound is in general 1-3moles, preferably 1-1,5 moles of the former to 1 mole of the aminecompound. Reaction may be carried out at an adequate temperature and, ingeneral, at a temperature from room temperature to the refluxtemperature of the solvent employed. The reaction duration mayadequately be chosen in accordance with the reaction condition and so onand may be terminated at a point at which the reaction yield becomeshighest. The above reactions may be carried out in a reaction solventbased on alcohol, such as methanol or ethanol, preferably at a lowtemperature in the presence of sodium borohydride.

[0212] The compound of the general formula (XIII) can be obtained easilyby oxidizing an acetophenone derivative substituted by R^(1′) and R^(2′)in a reaction medium of water or an organic solvent, for example,acyclic ether, such as dioxane or tetrahydrofuran, using an oxidizingagent, such as selenium dioxide. Alternatively, it can be produced bythe process described in J. Am. Chem. Soc., 79, 6562 (1957).

[0213] <<Production Process D>>

[0214] The compound represented by the general formula (I) in which R ishydrogen atom and R¹, R², R⁶, X, R⁷, R⁸, R⁹,

1 and

2 have the same meanings as those given previously can be obtained alsoby reacting an amine compound represented by the general formula (XIV).

[0215] in which R^(1′), R^(2′) and

1 have the same meanings as those given previously, with a compoundrepresented by the general formula (XV).

[0216] in which R⁶, X, R⁷, R^(8′), R^(9′) and

2 have the same meanings as those given previously and Z denotes aneliminable group, followed by deprotection of the protecting groups A,A″, A′″, that protecting the amino group in R^(3′) and the protectingacetyl group in R^(1′) by the method described in the paragraph“Production Process A”, with the proviso that the deprotection of theprotecting group A is unnecessary when R¹ is benzyloxy and theprotecting group A is benzyl.

[0217] By effecting the coupling reaction with the amine compound in anorganic solvent, if necessary, in the presence of a proton-acceptor,such as a tertiaryamine, for example, triethylamine, the compoundrepresented by the general formula (I) is obtained. The “eliminablegroup” means a group which is eliminated upon the above reaction of thechloride, bromide or iodide group or mesyl or tosyl group with, forexample, sulfonate or so on. The reaction may be realized, for example,using, in general, 1-10 moles of the amine compound represented by thegeneral formula (XIV) per one mole of the compound represented by thegeneral formula (XV).

[0218] Since this reaction proceeds at a lower velocity, the reactionmay preferably be effected in an autoclave in a reaction solvent, forexample, an alcohol, such as methanol, ethanol or butanol, a halogenatedhydrocarbon, such as methylene chloride or chloroform, ortetrahydrofuran or dioxane. The reaction temperature is chosen, ingeneral, in the range from 10 to 150° C., preferably from 70 to 130° C.The reaction duration is chosen, in general, in the range from 5 to 100hours.

[0219] The compound of the general formula (XIV) can be obtained byhydrogenating a substituted mandelonitrile substituted by R^(1′) andR^(2′) in the presence of a catalyst, such as Raney nickel. Thesubstituted mandelonitrile can be produced by a reaction of asubstituted benzaldehyde with hydrogen cyanide or with sodium cyanatetogether with sodium hydrogen sulfite as a racemic compound from whicheach optical active isomer can easily be separated by methods andtechniques employed commonly by preparing salts of the diastereomerswith an optically active acid selected adequately. The optically activesubstituted mandelonitrile derivative can be obtained by reacting theoptically active carboxylic acid resulting from hydrolysis of theoptically active substituted mandelonitrile with ammonia in the presenceof a commonly employed condensing agent, followed by reduction of theresulting product.

[0220] The compound of the general formula (XV) can be obtained byreacting a phenol compound represented by the general formula (VIII)with a compound represented by the general formula (XVI),

[0221] in which R⁶ and

2 have the same meanings as those given previously and B′ is a halogenatom, or with a compound represented by the general formula (XVII),

[0222] in which R⁶ and

2 have the same meanings as those given previously, under the conditionof synthesizing the compound represented by the general formula (III)described in the paragraph of “Production Process A”, followed bytosylating or metylating the alcohol resulting from the above reactionwith the compound represented by the general formula (XVI).

[0223] <<Production Process E>>

[0224] The compound represented by the general formula(I) in which R ismethyl can be produced by methylating the alcohol compound of thegeneral formula (I) in which R is hydrogen atom produced by the“Production Process” A, B, C or D under a commonly employed acidiccondition. Thus, the compound of the general formula (I) in which R ismethyl can be produce by treating, the compound of the general formula(I) in which R is hydrogen atom with hydrogen chloride in methanol at atemperature from room temperature to the boiling point of the reactionmedium.

[0225] The compound represented by the general formula(XVIII),

[0226] in which R^(1′), R^(2′), R⁶, Y′, X, R^(7′), R^(8′), R^(9′),

1 and

2 have the same meanings as those given previously, which is a compoundin which the amino group of the amine compound formed in the process forproducing the compound represented by the general formula (I) in which Ris hydrogen atom is protected by the protecting group Y′ and in which apossible protecting group A′ for the hydroxyl group, if present, isde-protected by the method described above, is processed by methylationof the hydroxyl group by a commonly used technique. By de-protecting theprotecting group Y′ for the amino group and those of A, A″, A′″ and thatprotecting the amino group in R^(3′), if present, as well as theprotecting acetyl group in R^(1′), with the proviso that thedeprotection of the protecting group A is unnecessary when R¹ isbenzyloxy and the protecting group A is benzyl, the compound representedby the general formula (I) in which R is methyl and R¹, R², R⁶, X, R⁷,R⁸, R⁹,

1 and

2 have the same meanings as those given previously is obtained.

[0227] A concrete example of methylation of the hydroxyl group consistsin that the compound is reacted with 1-5 equivalents of methyl iodide ormethyl bromide in the presence of a base, such as potassium carbonate,triethylamine, sodium hydroxide or sodium hydride, in a solvent, such asdimethylsulfoxide, dimethylformamide, dimethoxyethane ortetrahydrofuran, at a temperature in the range from room temperature tothe reflux temperature of the solvent. An alternative embodimentconsists in that the compound is reacted, in a form of its alkalinesolution containing sodium hydroxide or potassium hydroxide in water orin methanol, with 2-10 equivalents of dimethyl sulfate at a temperaturein the range from room temperature to the reflux temperature of thesolvent.

[0228] The starting compounds of the present invention may, ifnecessary, be purified, wherein known chromatographic techniquesincluding column-, flush column-, thin layer- and high performanceliquid chromatography may be employed therefor by taking into account ofsuch a parameter as the Rf value given in this specification.

[0229] As described above, the compound represented by the generalformula (I) may be present as four or two different isomers. The processaccording to the present invention can provide both the pure isomer andthe racemic mixture. The reactions described above do not alter thepertaining stereo chemistry.

[0230] Therefore., starting from the compound of the general formula (V)or of the general formula (XIII) having no asymmetric carbon atom,starting from the racemic compound represented by the general formula(II), (XII) or (XIV), or starting from the racemic compound representedby the general formula (III) or (XV), isomeric mixtures (R,R), (R,S),(S,S) and (S,R) are obtained. Similarly, starting from the pure isomerof the general formula (III) or (XV) and, for example, from the R-isomerof the general formula (III), mixtures of only two isomers (R,R) and(S,R) are obtained and, if an optical active isomer of the generalformula (I), (XII) or (XIV) is employed, corresponding pure isomer canbe obtained.

[0231] When a mixture of the four isomers or of two isomers is obtained,the isomers can be separated by a pertinent technique, such asfractional crystallization or the like, as their addition salts with anoptically active acid, such as camphor sulfonic acid, mandelic acid or asubstituted mandelic acid. The fractional crystallization may beperformed using an adequate solvent, preferably a lower alkanol, such asethanol or isopropanol or a mixture of them.

[0232] Every pair of the enantiomers can be separated into each opticalactive isomer by, for example, forming a diastereomeric salt andchromatographic separation on an optically active column, or by othermeans. When one of the starting raw materials is optically active, themixture of the diastereomers obtained as above can be divided into eachpure isomer. By separating each of the optical active isomers andpurifying it, it becomes possible to improve the pharmacological effector to eliminate side effects by using only the isomer having more higheractivity which is preferable as a medicament.

[0233] As the salt of the compound represented by the general formula(I) according to the present invention, there may be exemplified saltswith known acids, for example, addition salts thereof with mineral acidsand organic acids, such as hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen sulfuric acid, dihydrogen phosphoric acid, citric acid,maleic acid, tartaric acid, fumaric acid, gluconic acid and methanesulfonic acid: and with optically active acids, such as camphor sulfonicacid, mandelic acid and substituted mandelic acids, wherein specialpreference is given to those which are medicamentally acceptable.

[0234] For preparing a salt of the compound represented by the generalformula (I), the compound of the general formula (I) is dissolved in analcohol, such as methanol or ethanol, and the acid component is added tothe resulting alcoholic solution, whereby the corresponding acidaddition salt can be obtained. Examples of the acids to be used thereforinclude mineral acids and organic acids which are medicamentallyacceptable, such as hydrochloric acid, hydrobromic acid, sulfuric acid,hydrogen sulfuric acid, dihydrogen phosphoric acid, citric acid, maleicacid, tartaric acid, fumaric acid, gluconic acid and methane sulfonicacid.

[0235] The tricyclic compounds and the pharmacologically acceptablesalts according to the present invention have no recognizable toxicityand are useful as medicaments and exhibit, for example, p-activity, sothat they can be utilized as medicaments for therapeutic and preventivetreatments of β3-correlating diseases. The “β3-correlating diseases” isa generic expression for diseases which can be improved by a functionalactivity mediated β3-adrenaline receptor and include, for example,diabetes, obesity, hyperlipemia, diseasses in digestive system, such asabnormal motion and ulcer in digestive system, and depression. Inparticular, the compound according to the present invention serves fortreating diabetes, obesity and hyperlipemia. Thus, the compoundaccording to the present invention is effective as a medicament forpreventive or therapeutic treatment of diabetes due to its function fordecreasing the blood sugar value and is also effective for preventivetreatment of hyperlipemia and therapeutic treatment of obesity due toits lipolytic activity.

[0236] In preparing a medicament from the compound according to thepresent invention, it is preferable to admix, if necessary, to aneffective amount of the tricyclic compound represented by the generalformula(I) or salt thereof a pharmacologically acceptable carrier toformulate a drug composition. As the pharmacologically acceptablecarrier, there may be exemplified excipients, binding agents, such ascarboxymethylcellulose etc., disintegrator, lubricants and variousadditives.

[0237] For administering the drug containing the compound according tothe present invention to human, oral administration of the drug in aform of tablet, powder, granules, capsule, sugar-coated tablet, liquiddrug or syrup. Drugs for parenteral administration, such as injectiondrugs, may also be possible. The dose amount of administration may bedifferent in accordance with the age, body weight, significance of thedisease, symptom and so on and the dose may, in general, be in an amountof 0.01-2,000 mg per day for an adult all at once or allotted in severaladministrations. The term for receiving such drug may in general, rangefrom several weeks to several months with daily administration, while itis possible to increase or decrease both the term and the daily dose inaccordance with the state of the disease of patient.

THE BEST MODE FOR EMBODYING THE INVENTION

[0238] Below, the present invention will further be described by way ofExamples, wherein the present invention should not be understood asbeing restricted thereto.

[0239] For thin layer chromatography (TLC), Precoated Silica Gel 60 F254(of the firm Merck) was employed. After development with a mixed solventof chloroform/methanol (100/1-4/1) or ethyl acetate/n-hexane(100/0-1/10), confirmation by UV-irradiation (254 nm) and color reactionwith ninhydrin was performed. The Rf values of TLC cited refer to thoseof the free amines. For drying the organic solvent, anhydrous magnesiumsulfate or anhydrous sodium sulfate was used. A silica gel(Wako-gelC-200, a product of Wako Pure Chemical Ind., Ltd.) was used for thecolumn chromatography and Silica Gel 60 (230-400 mesh, a product of thefirm Merck) was used for the flush column chromatography. Pre-CoatedSilica Gel 60 F254 (20×20 cm, 2 mm; supplied from Merck) was used forthe parting thin layer chromatography. Elution was effected using amixed developer of chloroform/methanol (1/1).

[0240] For observing the nuclear magnetic resonance spectrum (NMR),Gemini-300 (FT-NMR; of the firm Varian) was employed. As the solvent,heavy chloroform was used so long as no special mention is made.Tetramethylsilane (TMIS) was used as the internal standard for thechemical shift which was recorded in terms of (δ ppm). The couplingconstant is indicated by J(Hz). For observing mass spectrum (MS).JEOL-JMS-SX102 was employed and the observation was made by fast atombombardment mass spectrum (FAB-MS). The results of the tests aresummarized in Table 1.

EXAMPLE 1

[0241](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamideHydrochloride

[0242] A. Synthesis of 2-benzyloxycarbonylamino-1-bromoethane(intermediate 0)

[0243] To a solution of 25 g of 2-bromoethylamine hydrochloride(supplied from Tokyo Chemical Industry Co.,Ltd.) and 34 ml oftriethylamine in 450 ml of methylene chloride, 19 ml ofbenzyloxycarbonyl chloride were added dropwise over a period of 20minutes under cooling by ice water with agitation, whereupon theagitation was continued for further 19 hours. The reaction mixture wasthen rinsed with water, saturated aqueous sodium bicarbonate solutionand saturated aqueous sodium chloride solution successively, whereuponthe organic layer was dried and the solvent was evaporated off under areduced pressure. The residue was cooled with ice water and the crystalswere filtered off and washed with hexane, whereby 29.4 g of theabove-identified compound were obtained. Rf=0.58 (chloroform).

[0244] B. Synthesis of 9H-2-(2-benzyloxycarbonylaminoethoxy)-carbazole(Intermediate 1)

[0245] To a solution of 252 mg of 2-hydroxycarbazole(supplied from thefirm Aldrich) and 292 mg of potassium carbonate in 4 ml ofdimethylformamide, 452 mg of the above Intermediate 0 were added and themixture was heated at 70° C. for 72 hours. To the reaction mixture,ethyl acetate and water were added to effect extraction and the organiclayer was rinsed with water and dried, from which the solvent wasdistilled off under a reduced pressure and the residue was purified by acolumn chromatography (with methanol/chloroform of 1/100), whereby 184.7mg of the above-identified compound were obtained. Rf=0.77(methanol/chloroform of 1/10).

[0246] C. Synthesis of 2-(9H-carbazol-2-yloxy)ethylamine (Intermediate2)

[0247] To 620 mg of Intermediate 1, 5 ml of 30% solution of hydrogenbromide in acetic acid were added and the mixture was agitated at roomtemperature for 1.5 hours. To the reaction mixture, diethylether wasadded under cooling with ice water and the deposited precipitate wasisolated by filtration. Water and NaOH were added to adjust the pH ofthe resulting mixture at 10, whereupon the mixture was subjected toextraction with ethyl acetate. The organic layer was dried and thesolvent was distilled off under a reduced pressure, whereby 311.3 mg ofthe above-identified compound were obtained. Rf=0.08(methanol/chloroform of 1/10).

[0248] D. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamideHydrochloride

[0249] To a solution of 500 mg of Intermediate 2 in a mixed solvent of40 ml of anhydrous acetonitrile and 4 ml of anhydrousdimethyl-formamide, 670 mg of2-bromo-1-[4-benzyloxy-3-[(methylsulfonyl)amino] phenyl]ethanone (70%purity)(Intermediate 3)[prepared by the method reported by A. A. Larsenet al. J. Med. Chem., 10, 462-472 (1967)] were added and the mixture wasagitated under argon atmosphere at 0° C. for 83 minutes.

[0250] This mixture was warmed to the room temperature(ca. 22° C.) andwas agitated for 79 minutes. To this mixture, a solution of 352 mg ofsodium borohydride in 30 ml of anhydrous ethanol were added at roomtemperature. After agitation for 81 minutes, the reaction was terminatedusing 1.0 N hydrochloric acid (pH 4) and thereto was added 0.89 g ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith 100 ml of ethyl acetate and the organic layer was rinsed withsaturated aqueous sodium chloride solution (three times with each 100ml) and was dried and concentrated under a reduced pressure to obtain1.09 g of a crude product.

[0251] This was purified by a column chromatography (ethyl acetate−1/8:methanol/chloroform), whereby 195 mg of the above-identified compound asfree amine were obtained. Rf=0.41 (methanol/chloroform of 1/10). To apart of this compound, 1.1 eq. of 0.1 N HCl/ethanol were added toconvert it into hydrochloride salt (the above-identified compound asfree amine were obtained. Rf=0.41 (methanol/chloroform Diethyl ether wasadded to the residue and the deposited precipitate was isolated byfiltration, washed with diethyl ether, dried under a reduced pressure at50° C., whereby 48.5 mg of the above-identified compound were obtainedas a powdery product.

EXAMPLE 2

[0252](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0253] 753 mg of hydrochloride salt of the compound of Example I weresubjected to hydrogenolysis using 406 mg of 10% palladium/carbon black(supplied from Merck) and 85 ml of methanol under 1 atm hydrogen gas(room temperature, 2.5 hours). The catalyst was filtered off on celiteand washed with chloroform and methanol. The filtrate and the washedliquor were brought together and the solvent was distilled off under areduced pressure, whereby 520 mg of the above-identified compound wereobtained as a pale yellow powdery product. Pf=0.11 (methanol/chloroformof 1/10).

EXAMPLE 3

[0254](±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamide

[0255] A. Synthesis of 3-hydroxydibenzofuran

[0256] To a solution of 1 g of 3-methoxydibenzofuran (provided from thefirm SALOR) in 5 ml of methylene chloride, 10.2 ml of 1 M solution ofboron tribromide in methylene chloride were added dropwise. The reactionmixture was agitated for 30 minutes under cooling with ice water and,then, warmed to room temperature and agitated further 35 minutes.Thereto were added 26 ml of water all at once and the mixture was causedto temperature elevation up to room temperature over a period of 30minutes with vigorous agitation. The organic layer was separated off andthe aqueous layer was extracted twice with methylene chloride. Theunited organic phase was rinsed with saturated aqueous sodium chloridesolution and dried and was then concentrated under a reduced pressure toobtain 663.1 mg of the above-identified compound.

[0257] B. Synthesis of 3-(2-benzyloxycarbonylaminoethoxy)-dibenzofuran(Intermediate 4)

[0258] Following the procedures given in the step B of Example 1, 321.3mg of 3-hydroxydibenzofuran, 541 mg of Intermediate 0 and 1,2 g ofpotassium carbonate were brought into reaction in 4.5 ml ofdimethylformamide. Thereto were added ethyl acetate and water to effectextraction and the organic layer was rinsed with water and dried, fromwhich the solvent was distilled off under a reduced pressure and theresidue was purified by a column chromatography (chloroform), whereby574.2 mg of the above-identified compound were obtained. Rf=0.40(chloroform).

[0259] C. Synthesis of 2-(dibenzofuran-3-yloxy)ethylamine (Intermediate5)

[0260] Following the procedures of step C in Example 1, 7 ml of 30%solution of hydrogen bromide in acetic acid were added to 554.7 mg ofIntermediate 4 and the mixture was agitated at room temperature for 1hour. Thereto was added diethyl ether under cooling with ice and thedeposited precipitate was isolated by filtration. Thereto were addedwater and NaOH to adjust the pH of the mixture at 10, whereupon themixture was subjected to extraction with ethyl acetate. The organiclayer was dried and the solvent was distilled off under a reducedpressure, whereby 224.6 mg of the above-identified compound wereobtained. Rf=0.13 (methanol/chloroform of 1/10).

[0261] D. Synthesis of (±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-methanesulfonamide

[0262] By a modification of the procedures described in the step D ofExample 1, a solution of 227 mg of Intermediate 3 (70% purity) was addedto a solution of 91.6 mg of Intermediate 5 in a mixed solvent composedof 4 ml of anhydrous acetonitrile and 1 ml of anhydrousdimethylformamide under argon atmosphere at 0° C. and thereto werefurther added 56.3 μl of triethylamine, whereupon the resulting mixturewas warmed to the room temperature (ca. 22° C.) and was agitated for 50minutes. To this mixture, a solution of 80 mg of sodium borohydride in 4ml of anhydrous ethanol was added at room temperature. After agitationfor 77 minutes, the reaction was terminated using 1 N hydrochloric acid(pH 4) and thereto were added 123 μl of ethanolamine. After agitationfor 10 minutes, the mixture was diluted with ethyl acetate and theorganic layer was rinsed thrice with saturated aqueous sodium chloridesolution and was dried and concentrated under a reduced pressure toobtain a crude product. This was purified by a column chromatography(chloroform−3/100: methanol/chloroform), whereby 52.4 mg of theabove-identified compound were obtained. Rf=0.37 (methanol/chloroform of3/100).

EXAMPLE 4

[0263](±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0264] Following the procedures of Example 2, 52.4 mg of the compound ofExample 3 were subjected to a hydrogenolysis under 1 atm hydrogen gasusing 30 mg of 10% palladium/carbon black and 6.4 ml of methanol with4.7 μl of acetic acid (room temperature, 1 hour). The catalyst wasfiltered off on celite and was then washed with chloroform and methanol.The filtrate and the washed liquor were brought together, from which thesolvent was distilled off. To the resulting residue, ethyl acetate andsaturated aqueous sodium bicarbonate solution were added to carry outextraction and the organic layer was dried, from which the solvent wasdistilled off under a reduced pressure. The resulting product wasconverted into hydrochloride salt by adding thereto 1.1 eq. of 0.1 Nhydrochloric acid/ethanol, whereby 43.3 mg of the above-identifiedcompound were obtained as a pale orange powdery product.Rf=0.07(methanol/chloroform of 1/10).

EXAMPLE 5

[0265](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0266] 2-bromo-1-[4-fluoro-3-[(methylsulfonyl)amino]phenyl] ethanone wasprepared in accordance with the procedures for the synthesis ofIntermediate 3 (with subsequence steps A, B, C and D).

[0267] A. Synthesis of 1-(4-fluoro-3-nitrophenyl)ethanone (Intermediate6)

[0268] 13.8 g of 4′-fluoroacetophenone (provided from Tokyo ChemicalIndustry Co., Ltd.) were added in two portions to 100 ml of fumingnitric acid cooled to −10° C. with agitation. After the mixture waswarmed to room temperature, the agitation was continued for further 4hours. This mixture was poured into 1.0 liter of ice water and wasextracted with 500 ml of ethyl acetate. The organic layer was dried andthe solvent was distilled off under a reduced pressure. The residue waspurified by a column chromatography (9/1-4/1: n-hexane/ethyl acetate)twice, whereby 4.16 g of the above-identified were obtained. Rf=0.50(chloroform).

[0269] B. Synthesis of 1-(3-amino-4-fluorophenyl)ethanone (Intermediate7)

[0270] To a solution of 4.16 g of Intermediate 6 in 305 ml of methanolwhich had been purged with argon, 189.7 mg of palladium oxide were addedand the mixture was subjected to reduction under 1 atm hydrogen gas atroom temperature. After agitation for 6 hours, the reaction system wasreplaced with argon and the reaction mixture was diluted with chloroformand was filtered. The solvent was evaporated off under a reducedpressure, whereby 3.52 g of the above-identified compound were obtained.Rf=0.47 (ethyl acetate/n-hexane of 1/1).

[0271] C. Synthesis of1-[4-fluoro-3-[(methylsulfonyl)amino]-phenyl]ethanone (Intermediate 8)

[0272] To a solution of 3.48 g of the Intermediate 7 in 100 ml ofpyridine, 1.93 ml of methanesulfonyl chloride were added at roomtemperature. After agitation for 2.5 days, the reaction mixture waspoured into saturated aqueous ammonium chloride solution and wassubjected to extraction with 200 ml of ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride solution (three timeswith 100 ml) and dried and the solvent was distilled off under a reducedpressure to obtain a crude product. This was purified by a columnchromatography (1/1 of n-hexane/ethyl acetate), whereby 3.9 g of theabove-identified compound were obtained. Rf=0.23 (ethyl acetate/n-hexaneof 1/1).

[0273] D. Synthesis of2-bromo-1-[4-fluoro-3-[(methylsulfonyl)-amino]phenyl]ethanone(Intermediate 9)

[0274] To a solution of 3.9 g of Intermediate 8 in 50 ml of 1,4-dioxane,2.83 g of bromine were added with agitation. The resulting mixture waswarmed to 60° C. and was agitated for 1 hour. After having been cooledto room temperature, the mixture was subjected to evaporation under areduced pressure. Water was added to the resulting residue and thedeposited precipitate was crushed and was filtered off, which was washedwith cold ethanol. After drying and recrystallization from ethanol, 3.69g of the above-identified compound were obtained. Rf=0.30 (with thricedevelopments; ethyl acetate/n-hexane of 1/2).

[0275] E. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethy]-2-fluorophenyl]methanesulfonamideHydrochloride

[0276] According to a modification of procedures described in the step Dof Example 1, a solution of 310 mg of Intermediate 9 in 3 ml ofanhydrous acetonitrile was added to a solution of 226 mg of Intermediate2 in a mixed solvent composed of 20 ml of anhydrous acetonitrile and 2ml of anhydrous dimethylformamide under argon atmosphere at 0° C. andthereto were added 103 μl of triethylamine, whereupon the mixture waswarmed to the room temperature (ca. 22° C.) and was agitated for 50minutes.

[0277] To this mixture was added a solution of 189 mg of sodiumborohydride in 15 ml of anhydrous ethanol at room temperature. Afteragitation for 77 minutes, the reaction was terminated using 1 Nhydrochloric acid (pH 4) and, then, 479 μl of ethanolamine were addedthereto. After agitation for 10 minutes, the resulting mixture wasdiluted with ethyl acetate and the organic layer was rinsed withsaturated aqueous sodium chloride solution three times, whereupon it wasdried and subjected to evaporation under a reduced pressure to obtain acrude product. This was purified by a column chromatography(chloroform−3/100: methanol/chloroform), whereby 239.8 mg of free amineproduct of the above-identified compound were obtained. To this product,1.1 eq. of 0.1 N hydrochloric acid/ethanol were added to convert it intohydrochloride salt (the above-identified compound) and the solvent wasdistilled off under a reduced pressure. Diethyl ether was added to theresulting residue and the deposited precipitate was filtered off,followed by washing with hot ethanol and drying at 50° C. under reducedpressure to obtain 121.1 mg of the above-identified compound as apowdery product. Rf=0.37 (methanol/chloroform of 1/6).

EXAMPLE 6

[0278](±)N-[5-[2[2(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0279] 2-bromo-1-[4-chloro-3-[(methylsulfonyl)amino]phenyl]ethanone wasprepared in a manner similar to the synthesis method of Intermediate 3and in the same manner as in the steps A. B. C and D of Example 5.

[0280] A. Synthesis of 1-(4-chloro-3-nitrophenyl)ethanone (Intermediate10)

[0281] 15.5 g of 4′-chloroacetophenone (Tokyo Chemical Industry Co.,Ltd.) were added in two portions to 100 ml of fuming nitric acid cooledto −10° C. with agitation. The resulting mixture was warmed to roomtemperature and was agitated for four hours. This mixture was pouredinto 1.6 liters of ice water and was then subjected to extraction with800 ml of ethyl acetate. The organic layer was separated and dried andthe solvent was evaporated off under a reduced pressure. The resultingresidue was purified by a column chromatography (9/1-4/1:n-hexane/ethylacetate), whereby 1.2 g of the above-identified compound were obtained.Rf=0.52 (chloroform).

[0282] B. Synthesis of 1-(3-amino-4-chlorophenyl)ethanone (Intermediate11)

[0283] To a solution of 1.2 g of Intermediate 10 in 260 ml of methanol,7.63 g of tin (II) chloride and 5.48 ml of concentrated hydrochloricacid were added and the mixture was agitated at room temperature for 3.5hours. The mixture was concentrated and washed with saturated aqueoussodium bicarbonate solution and was then subjected to extraction withethyl acetate. The organic layer was concentrated under a reducedpressure, whereby 970 mg of the above-identified compound were obtained.Rf=0.49 (ethyl acetate/n-hexane of 1/1).

[0284] C. Synthesis of1-[4-chloro-3-[(methylsulfonyl)amino]-phenyl]ethanone (Intermediate 12)

[0285] To a solution of 970 mg of the Intermediate 11 in 50 ml ofpyridine, 487 μl of methanesulfonyl chloride were added at roomtemperature. After agitation for 2.5 days, the reaction mixture waspoured into saturated aqueous ammonium chloride solution and wassubjected to extraction with 100 ml of ethyl acetate. The organic layerwas rinsed with saturated aqueous sodium chloride solution (three timeswith 50 ml) and dried and concentrated under a reduced pressure toobtain a crude product. This was purified by a column chromatography(n-hexane/ethyl acetate of 3/2-1/1), whereby 890 mg of theabove-identified compound were obtained. Rf=0.41 (ethyl acetate/n-hexaneof 1/1).

[0286] D. Synthesis of2-bromo-1-[4-chloro-3-[(methylsulfonyl)-amino]phenyl]ethanone(Intermediate 13)

[0287] To a solution of 890 mg of Intermediate 12 in 10 ml of1,4-dioxane. 605 mg of bromine Were added with agitation. The resultingmixture was warmed to 60° C. and was agitated for 1 hour.

[0288] After having been cooled to room temperature, the mixture wasconcentrated under a reduced pressure. Water was added to the resultingresidue and the deposited precipitate was crushed and filtered off,which was washed with cold ethanol. After drying and recrystallizationfrom ethanol, 620 mg of the above-identified compound were obtained.Rf=0.39 (ethyl acetate/n-hexane of 1/1).

[0289] E. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethy]-2-chlorophenyl]methanesulfonamideHydrochloride

[0290] According to a modification of procedures described in the step Dof Example 1, a solution of 327 mg of Intermediate 13 in 3 ml ofanhydrous acetonitrile was added to a solution of 226-mg of Intermediate2 in a mixed solvent composed of 20 ml of anhydrous acetonitrile and 2ml of anhydrous dimethylformamide under argon atmosphere at 0° C. andthereto were added 103 μl of triethylamine, whereupon the mixture waswarmed to the room temperature (ca. 22° C.) and was agitated for 50minutes.

[0291] To this mixture was added a solution of 189 mg of sodiumborohydride in 15 ml of absolute ethanol at room temperature. Afteragitation for 77 minutes, the reaction was terminated using 1 Nhydrochloric acid (pH 4) and, then, 479 μl of ethanolamine were addedthereto. After agitation for 10 minutes, the resulting mixture wasdiluted with ethyl acetate and the organic layer was rinsed withsaturated aqueous sodium chloride solution three times, whereupon it wasdried and subjected to evaporation under a reduced pressure to obtain acrude product. This was purified by a column chromatography (1/9-1/6:methanol/chloroform), whereby 129.8 mg of free amine product of theabove-identified compound were obtained. Rf=0.36 (methanol/chloroform of1/6).

[0292] To this product, 1.1 eq. of 0.1 N hydrochloric acid/ethanol wereadded to convert it into hydrochloride salt (the above-identifiedcompound) and the solvent was distilled off under a reduced pressure.Diethyl ether was added to the resulting residue and the depositedprecipitate was filtered off, followed by washing with hot ethanol anddrying at 50° C. under reduced pressure to obtain 34.1 mg of theabove-identified compound as a powdery product.

EXAMPLE 7

[0293](±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0294] To a solution of 219.5 mg of Intermediate 2 in a mixed solvent of20 ml of anhydrous acetonitrile and 2 ml of anhydrous dimethylformamide,163.6 mg of 2-bromo-1-[3-(methylsulfonyl)aminophenyl]ethanone(Intermediate 14) [prepared by the method reported by A. A. Larsen etal, J. Med. Chem., 9, 88-97 (1966)] were added and the mixture wasagitated under argon atmosphere at 0° C. for 83 minutes.

[0295] This mixture was warmed to the room temperature (ca. 22° C.) andwas agitated for 79 minutes. To this mixture, a solution of 110 mg ofsodium borohydride in 10 ml of absolute ethanol were added at roomtemperature. After agitation for 81 minutes, the reaction was terminatedusing 1.0 N hydrochloric acid (pH 4) and thereto was added 0.28 ml ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith 30 ml of ethyl acetate and the organic layer was rinsed withsaturated aqueous sodium chloride solution three times and was dried andconcentrated under a reduced pressure to obtain 399 mg of a crudeproduct. This was purified by a PTLC (developed with methanol/chloroformof 1/8), whereby 48.3 mg of the free amine were obtained. Rf=0.32(methanol/chloroform of 1/4).

[0296] 1.1 eq. of 0.1 N HCl/ethanol were added to convert it intohydrochloride salt (the above-identified compound) and the solvent wasdistilled off under a reduced pressure. Diethyl ether was added to theresidue and the deposited precipitate was recrystallized from diethylether and dried under a reduced pressure at 50° C. whereby 38.7 mg ofthe above-identified compound were obtained as a powdery product.

EXAMPLE 8

[0297](±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]phenylmethanesulfonamideHydrochloride

[0298] A. Synthesis of 1-[3-benzylsulfonylamino)phenyl]ethanone(intermediate 15)

[0299] Following the procedures of synthesis of Intermediate 14 inExample 7, 719 mg of the above-identified compound were prepared from300 mg of 3′-aminoacetophenone (Tokyo Chemical Industry Co., Ltd.), 427mg of benzylsulfonylchloride (Tokyo Chemical Industry Co., Ltd.) and 3ml of pyridine.

[0300] B. Synthesis of 2-bromo-1-[3-(benzylsulfonylamino)phenyl]ethanone (Intermediate 15-1)

[0301] Following the procedures of Example 7, 130 μl of bromine wereadded to a solution of 700 mg of the Intermediate 15 in 6.8 ml of1,4-dioxane to cause reaction, whereby a fraction containing theabove-identified compound (786 mg) was obtained. This showed in 1H-NMR(300 MHz, CDCl₃) a integrated ratio of 29% of the monobromide isomer,58% of dibromide isomer and 13% of unreacted starting compound. Theproduct was served in the form of mixture as such for the subsequentreaction.

[0302] C. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]phenylmethanesulfonamide Hydrochloride

[0303] A solution of 465 mg of Intermediate 15-1 (58%purity) in 10 ml ofanhydrous acetonitrile was added to a solution of 400 mg of Intermediate2 in a mixed solvent composed of 40 ml of anhydrous acetonitrile and 4ml of anhydrous dimethylformamide under argon atmosphere at 0° C. andthe mixture was agitated for 80 minutes.

[0304] The mixture was warmed to the room temperature (ca. 22° C.) andwas agitated for further 7.0 minutes. To this mixture was added asolution of 244 mg of sodium borohydride in 20 ml of absolute ethanol atroom temperature. After agitation for 60 minute, the reaction wasterminated using 1.0 N hydrochloric acid (pH 4) and thereto was addedethanolamine. After agitation for 10 minutes, the mixture was dilutedwith 60 ml of ethyl acetate and was-rinsed with 60 ml of water,whereupon the organic layer was washed twice with saturated aqueoussodium chloride solution and was, after drying, subjected to evaporationunder a reduced pressure to obtain a crude product. This was purified bya PTLC (developed with methanol/chloroform of 1/8), whereby 66 mg offree amine compound were obtained. Rf=0.16 (methanol/chloroform of1/10).

[0305] This was converted into hydrochloride salt (the above-identifiedcompound) by adding 1.1 eq. of 0.1 N hydrogen chloride/ethanol,whereupon the solvent was distilled off under a reduced pressure. To theresidue was added diethyl ether and the deposited precipitate wasstashed with diethyl ether and dried at 46° C. under a reduced pressure,whereby 60 mg of the above-identified compound were obtained as apowdery, product.

EXAMPLE 9

[0306](±)-N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0307] Following the procedures of Example 7, the above-identifiedcompound was synthesized from 224.6 mg of Intermediate 5 and 170 mg ofIntermediate 14, with the proviso that the following modification wasincorporated. Thus, addition of dimethylformamide was omitted and thepurification of the crude product was effected twice by a chromatography(methanol/chloroform of 1/20-1/10). The free amine compound (98.4 mg)was converted into its hydrochloride salt (the above-identifiedcompound) with 1.1 eq. of 0.1 N hydrogenchloride/ethanol, whereupon thesolvent was evaporated off under a reduced pressure. To the resultingresidue was added diethyl ether and the deposited precipitate was washeddiethyl ether and dried under a reduced pressure at 46° C. whereby theabove-identified compound was obtained as a powdery product. Rf=0.27(methanol/chloroform of 1/10).

EXAMPLE 10

[0308](±)-N-[3-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0309] A. Synthesis ofN-[7-[2-[(benzyloxycarbonyl)aminolethoxy]-9H-fluoren-2-yl]acetamide(Intermediate 16)

[0310] Following the procedures of the step B of Example 1, 300 mg of2-acetamide-7-hydroxyfluorene (supplied from the firm SALOR). 485.5 mgof intermediate 0 and 241.2 mg of potassium carbonate were brought intoreaction in 3 ml of dimethylformamide (heated at 70° C. for 24 hours).To the reaction mixture, ethyl acetate and water were added to subjectto extraction and the organic layer was rinsed with water and dried,whereupon the solvent was distilled off and the residue was purified bya column chromatography (methanol/chloroform of 1/20) to obtain 431.9 mgof the above-identified compound. Rf=0.47 (methanol/chloroform of 1/10).

[0311] B. Synthesis of N-[9H-7-(2-aminoethoxy)fluorene]-2-acetamide(Intermediate 17)

[0312] Following the procedures of step C of Example 1, 5 ml of 30%solution of hydrogen bromide in acetic acid were added to 572.9 mg ofIntermediate 16 and the mixture was agitated at room temperature for 1hour. Thereto was added diethyl ether under cooling with ice and thedeposited precipitate was isolated by filtration. Water and NaOH wereadded to adjust the pH of the mixture at 10, whereupon the mixture wassubjected to extraction with ethyl acetate. The organic layer was driedand the solvent was distilled off under a reduced pressure, whereby256.7 mg of the above-identified compound were obtained.Rf=0.06(methanol/chloroform of 1/5).

[0313] C. Synthesis of(±)-N-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0314] Following the procedures of Example 7, the above-identifiedcompound was synthesized from 253.2 mg of Intermediate 17 and 154.1 mgof Intermediate 14, with the proviso that the following modification wasincorporated. Thus, addition of dimethylformamide was omitted and thepurification of the crude product was effected by a chromatography(methanol/chloroform of 1/10) and a PTLC (development withmethanol/chloroform of 1/5). The free amine compound (52.3 mg) wasconverted into its hydrochloride salt (the above-identified compound)with 1.1 eq. of 0.1 N hydrogen chloride/ethanol, whereupon the solventwas evaporated off under a reduced pressure. To the resulting residuewas added diethyl ether and the deposited precipitate was washed diethylether and dried under a reduced pressure at 46° C., whereby theabove-identified compound (45.1 mg) was obtained as a powdery product.Rf=0.40 (methanol/chloroform of 1/5).

EXAMPLE 11

[0315](±)-N-[3-[2-[[1-(9H-carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0316] A. Synthesis of (R)-[1-(9H-carbazol-2-yloxy)propan-2-yl] amine(Intermediate 18)

[0317] 4.82 g of (R)-(−)-2-amino-1-propanol (supplied from the firmAldrich) were dissolved in 157 ml of tetrahydrofuran and thereto wereadded 13.84 g of di-tert-butyl-dicarbonate at room temperature and themixture was agitated for 18 hours. The solvent was evaporated off undera reduced pressure to obtain 11 g of a white solid product. 10.3 g ofthe above white solid product were dissolved together with 17.76 g oftriphenylphosphine in 147 ml of methylene chloride, whereto 9.3 g ofN-chlorosuccinimide were added in small portions under ice-cooling andthe mixture was agitated at room temperature for 23 hours. The reactionliquor was washed with an aqueous sodium hydroxide and saturated aqueoussodium chloride solution successively, followed by drying and distillingoff of the solvent under a reduced pressure. The residue was purified bya silica gel chromatography, whereby 5.89 g of(R)-2-(N-tert-butoxycarbonyl)amino-1-chloropropane were obtained.Rf=0.89 (methanol/chloroform of 1/9).

[0318] To a solution of 734 mg of 2-hydroxycarbazole and 815.6 mg of theabove compound in 9.6 ml of dimethylformamide, 1,588 mg of anhydrouspotassium carbonate and 190 mg of potassium iodide were added and thereaction and the after-treatment were performed in accordance with theprocedures of the synthesis method in the step B of Example 1, whereby597 mg of (R)-2-(N-tert-butoxycarbonylamino-1-propyloxy)carbazole wereobtained. Rf=0.81 (methanol/chloroform of 1/9).

[0319] To 597 mg of the above compound were added 10 ml of 30% solutionof hydrogen bromide in acetic acid and the reaction and after-treatmentwere effected in accordance with the procedures of the synthetic methodin the step C of Example 1, whereby 258 mg of Intermediate 18 wereobtained. Rf=0.06 (methanol/ethyl acetate of 1/10).

[0320] B. Synthesis of (±)-N-[3-[2-[[1-(9H-carbazol-2-yloxy)propan-2R-yl]amino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0321] The above-identified compound was synthesized in accordance withthe procedures of Example 7 by performing the reaction of theIntermediate 18 (120 mg) with Intermediate 14 (190 mg) and theafter-treatments, with the proviso that the following alterations wereincorporated. Thus, in the coupling reaction, 72 μl (1 eq.) oftriethylamine were used as the basic catalyst and the purification ofthe crude product was effected by a PTLC (with development withmethanol/ethyl acetate of 1/9). The free amine compound (87.5 mg) wasconverted into its hydrochloride salt (the above-identified compound)using 1.1 eq. of 0.1 N solution of hydrogen chloride/ethanol and thesolvent was distilled off under a reduced pressure. To the residue wasadded diethyl ether and the deposited precipitate was washed withdiethyl ether and dried at 46° C. under a reduced pressure, whereby 80.5mg of the above-identified compound was obtained as a powdery product.Rf=0.19 (methanol/ethyl acetate of 1/10).

EXAMPLE 12

[0322](R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0323] A. Synthesys of(R)-2-bromo-1-[3-nitro-4-(benzyloxy)-phenyl]ethanol (Intermediate 19)

[0324] To a solution of 1.01 g of 2-bromo-1-[3-nitro-4-(benzyloxy)phenyl]ethanone (70% purity) prepared according to the method reportedby C. Kaiser et al in J. Med. Chem. 17, 49 (1974) and 100 mg of (R)-3,3-diphenyl-1-methyltetrahydro-1H. 3H-pyrolo[1,2-c][1.3.2]oxazaborol [aproduct of Tokyo Chemical Industry Co., Ltd., referred to hereinafter asthe “asymmetric catalyst”; there are (R)- and (S)-modifications] in 20ml of anhydrous tetrahydrofuran (prepared upon use), 2.16 ml of a 2 Msolution of borane/dimethylsulfide complex in tetrahydrofuran (suppliedfrom the firm Aldrich) were added dropwise over a period of 5 minutesand the mixture was agitate at the same temperature for 2 hours.

[0325] The reaction mixture was diluted with ethyl acetate and theso-diluted mixture was washed with saturated aqueous ammonium chloridesolution and saturated aqueous sodium chloride successively, followed bydrying and evaporating off of the solvent under a reduced pressure. Theresidue was purified by a column chromatography (ethyl acetate/n-hexaneof 1/2-1/1), whereby 1.015 g of the above-identified compound wereobtained. Rf=0.41 (ethyl acetate/n-hexane of 1/1).

[0326] Retention time: 35.7 min. Analytical conditions: column:CHIRALCEL OB (4.6 mmø, 25 cm long; supplied from Daicel Chem. Ind.,Ltd.). Mobile phase: n-hexane/2-propanol (7/3); flow rate: 0.5 ml/min.;detection wave length: 254 nm; temperature: 35° C.

[0327] B. Synthesis of(R)-3-nitro-4-benzyloxy-[2-iodo-1-(triethylsilyloxy)ethyl]benzene(Intermediate 20)

[0328] To a solution of 695.6 mg of Intermediate 19 in 30 ml of acetone,2.96 g of sodium iodide (supplied from Wako Pure Chemical Ind., Ltd.)were added and the mixture was heated under reflux for 2 hours. Aftercooling to room temperature, the mixture was treated by filtration andthe solvent in the filtrate was evaporated off under a reduced pressure.To the resulting residue, chloroform and water were added and theorganic layer was rinsed with saturated aqueous sodium thiosulfatesolution and was dried, whereupon the solvent was evaporated off under areduced pressure. The resulting oily product (0.78 g), imidazole (408.5mg) and dimethylaminopyridine (24.4 mg) were dissolved in 5 ml ofdimethylformaide, whereto 452 mg of triethylsilane chloride were addedunder ice-cooling. Directly thereafter, the mixture was warmed to roomtemperature and was agitated for 1.5 hours. The resulting mixture wasdiluted with ethyl acetate and then rinsed with water, 2% aqueous coppersulfate solution, water and, finally, saturated aqueous sodium chloridesolution successively, followed by drying and distilling off of thesolvent under a reduced pressure. The residue was purified by a columnchromatography (ethyl acetate/n-hexane of 1/3), whereby 915 mg of theabove-identified compound were obtained. Rf=0.76(ethyl acetate/n-hexaneof 1/1).

[0329] C. Synthesis of(R)-N,N-[[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-nitro-4-(benzyloxy)phenyl]]ethyl]amine(Intermediate 21)

[0330] A solution of 289 mg of Intermediate 20, 165 mg of Intermediate 2and 0.51 ml of Huenig base (supplied from the firm Aldrich) in 1.5 ml ofdimethylacetamide was agitated for 8 hours at 60° C. To the resultingreaction mixture, 40 ml of ethyl acetate and 40 ml of water were addedto effect extraction, whereupon the aqueous layer was further extractedwith ethyl acetate three times. The united organic phase was dried andthe solvent was distilled off under a reduced pressure. The residue waspurified by a column chromatography(chloroform−methanol/chloroform=1/49), whereby 173 mg of theabove-identified compound were obtained. Rf=0.60 (methanol/chloroform of1/9).

[0331] D. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-nitro-4-(benzyloxy)phenyl]]ethyl]amine (Intermediate 22)

[0332] 173 mg of the above amine compound were dissolved in 2 ml ofmethylene chloride and thereto were added 45 μl of triethylamine and themixture was agitated under ice-cooling and thereto were added 43 μl ofbenzylchloroformate (supplied from the firm Aldrich). After agitationfor 30 minutes, the mixture was agitated for 8 hours at roomtemperature. The mixture was then diluted with ethyl acetate and rinsedwith water and, then, with saturated aqueous sodium chloride solution,successively, followed by drying and distilling off of the solvent undera reduced pressure. The residue was purified by a column chromatography(ethyl acetate/n-hexane=1/5-1/3), whereby 200 mg of the above-identifiedcompound were obtained. Rf=0.55 (ethyl acetate/n-hexane of 1/2).

[0333] Retention time 14.7 min. Analytical conditions: column CHIRALCELOJ-R (4.6 mmø, 15 cm long; supplied from Daicel. Chem. Ind., Ltd.):mobile phase: 0.5 M NaClO₄/CH₃CN=20/80; flow rate: 0.7 ml/min.;detection wave length: 254 mm: temperature: 30° C.

[0334] E. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-amino-4-(benzyloxy)phenyl]]ethyl]amine (Intermediate 23)

[0335] To a solution of 200 mg of the above nitro compound in 14 ml ofmethanol which had been purged by argon, 5 mg of platinum oxide(anhydrous, supplied from Wako Pure Chem. Ind., Ltd.) were added and thecompound was reduced under 1 atm. hydrogen gas under ice-cooling. Afteragitation for 6 hours, the reaction system was replaced by argon and thereaction mixture was diluted with chloroform and filtered. The solventwas evaporated under reduced pressure, whereby 183 mg of theabove-identified compound were obtained. Rf=0.32 (ethyl acetate/n-hexaneof 1/3).

[0336] F. Synthesis of(R)-N-[5-[2-[benzyloxycarbonyl-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(triethylsilyloxy)ethyl]-2-(benzyloxy)phenyl]methanesulfonamide(Intermediate 24)

[0337] To a solution of 183 mg of the above amine compound in 1 ml ofpyridine, 20 μl of methanesulfonyl chloride were added and the mixturewas agitated for 1 hours, whereto water was added and the resultingmixture was agitated for 3 hours, before the mixture was ice-cooled andthe thereby deposited precipitate was separated by filtration. Theprecipitate was dissolved in ethyl acetate and the organic layer wasrinsed with saturated aqueous sodium chloride solution and dried,whereupon the solvent was distilled off under a reduced pressure toobtained 192 mg of the above-identified compound. Rf=0.44 (ethylacetate/n-hexane of 1/2).

[0338] G. Synthesis of (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0339] In accordance with the procedures of the step C in Example 1, thebenzyloxycarbonyl group and the triethylsilyl group were eliminatedusing 192 mg of the above methanesulfonamide compound with 4 ml of 30%solution of hydrogen bromide in acetic acid. Then, in accordance withthe procedures of the step E in Example 1, the benzyl group wassubjected to hydrogenolysis under a hydrogen atmosphere using 71 mg of10% palladium carbon black (supplied from Merk), followed by conversioninto hydrochloride salt by means of a usual technique, whereby theabove-identified compound was obtained.

[0340] Retention time: 40.6 min. Analytical conditions: column CHIRALCELOJ-R (supplied from Daicel Chem. Ind., Ltd.); mobile phase 0.5 MNaClO₄/CH₃CN=77/23; flow rate: 0.5 ml/min. detection wave length: 254nm; temperature: 40° C.

EXAMPLE 13

[0341](S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0342] The reactions and the after-treatments were performed in the samemanner as in Example 12, except that an asymmetric catalyst of(S)-modification (supplied from Tokyo Chemical Industry Co., Ltd.) wasused.

[0343] A. Synthesis of(S)-2-bromo-1-[3-nitro-4-(benzyloxy)-phenyl]ethanol

[0344] Retention time: 47.3 min. Analytical conditions: column:CHIRALCEL OB (supplied from Daicel Chem. Ind., Ltd.); mobile phasen-hexane/2-propanol =7/3; flow rate: 0.5 ml/min.; detection wave length:254 nm; temperature: 35° C.

[0345] D. Synthesis of(S)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-[3-nitro-4-(benzyloxy)phenyl]]ethyl]amine

[0346] Retention time: 9.8 min. Analytical conditions: column: CHIRALCELOJ-R (supplied from Daicel Chem. Ind., Ltd.); mobile phase: 0.5 MNaClO₄/CH₃CN 2/8; flow rate: 0.7 ml/min.; detection wave length: 254 mm;temperature: 30° C.

[0347] G. Synthesis of (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyefthyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0348] Retention time: 47.5 min. Analytical conditions: column CHIRALCELOJ-R (supplied from Daicel Chem. Ind., Ltd.): mobile phase 0.5 MNaClO₄/CH₃CN=77/23; flow rate: 0.5 ml/min.; detection wave length: 254nm; temperature: 40° C.

EXAMPLE 14

[0349](R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0350] The synthesis was performed in accordance with the procedures asgiven in Example 12 except that the hydrogenolysis with 10%palladium/carbon black in the step G of Example 12 was not incorporated.

[0351] A. Synthesis of (R)-2-bromo-1-(3-nitrophenyl)ethanol(Intermediate 25)

[0352] To a solution of 769 mg of 2-bromo-1-[3′-nitrophenyl]ethanone and100 mg of the said asymmetric catalyst [(R)-modification; supplied fromTokyo Chemical Industry Co. Ltd.] in 20 ml of anhydrous tetrahydrofuran(prepared on each use), 2.16 ml of a 2 M solution of borane/dimethylsulfide complex in tetrahydrofuran (supplied from the firm Aldrich) wereadded dropwise over a period of 5 minutes, whereupon the reaction andthe after-treatments were performed, whereby 768 mg of theabove-identified compound were obtained. Rf=0.72 (ethyl acetate/n-hexaneof 1/1).

[0353] Retention time: 9.02 min. Analytical conditions: column CHIRALCELAD (supplied from Daicel Chem. Ind., Ltd.); mobile phasen-hexane/2-propanol (1/1); flow rate: 0.5 ml/min.; detection wavelength: 254 nm; temperature: 35° C.

[0354] B. Synthesis of(R)-3-[2-iodo-1-(triethylsilyloxy)ethyl]-nitrobenzene (Intermediate 26)

[0355] To a solution of 768 mg of Intermediate 25 in 30 ml of acetone,2.96 g of sodium iodide (supplied from Wako Pure Chemical Ind. Ltd.)were added, followed by reaction and after-treatment. 795 mg of theresulting product, 408.5 mg of imidazole and 24.4 mg ofdimethylaminopyridine were dissolved in 5 ml of dimethylformaide,whereto 452 mg of triethylsilane chloride were added under ice-cooling,followed by reaction and after-treatment, whereby 994 mg of theabove-identified compound were obtained. Rf=0.43 (ethyl acetate/n-hexaneof 1/3).

[0356] C. Synthesis of(R)-N,N-[[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-(3-nitrophenyl)ethyl]amine(Intermediate 27)

[0357] A solution of 451 mg of Intermediate 26, 330 mg of Intermediate 2and 1.02 ml of Hunig base (supplied from the firm Aldrich) in 2 ml ofdimethylformamide was subjected to reaction and after-treatment, whereby217 mg of the above-identified compound were obtained.

[0358] D. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyloxy)-2-(3-nitrophenyl)]ethyl]amine(Intermediate 27)

[0359] 217 mg of the above amine compound were dissolved in 2 ml ofmethylene chloride and thereto were added 66 μl of triethylamine withsubsequent agitation under ice-cooling and further addition of 63 μl ofbenzyl chloroformate (supplied from the firm Aldrich), followed byreaction and after-treatment, whereby 261 mg of the above-identifiedcompound were obtained. Rf=0.32 (ethyl acetate/n-hexane of 1/2).

[0360] E. Synthesis of(R)-N,N,N-[(benzyloxycarbonyl)-[2-(9H-carbazol-2-yloxy)ethyl]-[2-(triethylsilyoxy)-2-(3-aminophenyl)]ethyl]amine

[0361] To a solution of 261 mg of the above nitro compound in 5.5 ml ofmethanol which had been purged by argon, 5 mg of platinum oxide(anhydrous, supplied from Wako Pure Chem. Ind., Ltd.) were added toeffect reduction with 1 atm. hydrogen gas, followed by after-treatmentto obtain 236 mg of the above-identified compound.

[0362] F. Synthesis of(R)-N-[3-[2-[benzyloxycarbonyl-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(triethylsilyloxy)-ethyl]phenyl]methanesulfonamide(Intermediate 28)

[0363] To a solution of 236 mg of te above amine compound in 1 ml ofpyridine, 30 μl of methanesulfonyl chloride were added to causereaction, followed by after-treatment to obtain 253 mg of theabove-identified compound. Rf=0.25 (ethyl acetate/n-hexane of 1/2).

[0364] G. Synthesis of(R)-N-[3-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0365] According to the procedures of the step C in Example 1, the abovemethanesulfonamide compound was processed by adding to 253 mg thereof 5ml of 30% solution of hydrogen bromide in acetic acid to cause reaction,followed by after-treatment to obtain the above-identified compound.

[0366] Retention time: 29.3 min. Analytical conditions: column:CHIRALCEL OJ-R (supplied from Daicel Chem. Ind., Ltd.); mobile phase 0.5M NaClO₄/CH₃CN=7/3; flow rate: 0.5 ml/min.; detection wave length: 254nm; temperature: 30° C.

EXAMPLE 15

[0367](S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0368] The reactions and the after-treatments were performed in the samemanner as in Example 14, except that an asymmetric catalyst of(S)-modification (supplied from Tokyo Chemical industry Co., Ltd.) wasused.

[0369] A. Synthesis of (S)-2-bromo-1-(3-nitrophenyl)ethanol

[0370] Retention time: 8.18 min. Analytical conditions: column:CHIRALCEL AD (supplied from Daicel Chem. Ind., Ltd.); mobile phasen-hexane/ethanol=1/1; flow rate: 0.5 ml/min.; detection wave length: 254nm; temperature: 35° C.

[0371] G. Synthesis of (S)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide Hydrochloride

[0372] Retention time: 25.3 min. Analytical conditions: column:CHIRALCEL OJ-R (supplied from Daicel Chem. Ind., Ltd.); mobile phase:0.5 M NaClO₄/CH₃CN=7/3; flow rate: 0.5 ml/min.; detection wave length:254 nm; temperature: 30° C.

EXAMPLE 16

[0373](±)-N-methyl-3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]benzenesulfonamideHydrochloride

[0374] A. Synthesis of N-methyl-3-acetylbenzenesulfonamide

[0375] To a solution of 2 g of 3-acetylbenzenesulfonyl fluoride(supplied from the firm Acros) in 20 ml of pyridine, 2,02 ml of 40%methylamine/methanol (supplied from Wako Pure Chem. Ind. Co., Ltd.) wereadded at room temperature and the mixture was agitated for 2 hours.There were replenished 2.02 ml of 40% methylamine/methanol and theagitation was continued for further 40 minutes. Thereto were added 5 Nhydrochloric acid and about 40 ml of water to terminate the reaction (pH4) and the product was extracted with ethyl acetate. The organic layerwas separated and dried and the solvent was distilled off under areduced pressure, whereby 996 mg of the above-identified compound wereobtained. Rf=0.64 (methanol/chloroform of 1/10).

[0376] B. Synthesis of N-methyl-3-(2-bromoacetyl)benzenesulfonamide(Intermediate 29)

[0377] To a solution of 990 mg of the above-obtained compound in 15.8 mlof 1,4-dioxane, 769 mg of bromine were added and the mixture was stirredfor 1 hour at 60° C. The mixture was concentrated under a reducedpressure, followed by addition of 18 ml of water to the residue,whereupon the resulting mixture was agitated vigorously underice-cooling. The deposited precipitate was triturated and separated byfiltration and was washed with water. The separated product was driedunder a reduced pressure at room temperature, whereby 1.18 g of theabove-identified compound were obtained. Rf=0.63 (methanol/chloroform of1/10).

[0378] C. Synthesis of(±)-N-methyl-3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]benzenesulfonamideHydrochloride

[0379] According to the procedures described in the step D of Example 1,0.59 g of the above Intermediate 29, 0.59 g of HBr-addition salt ofIntermediate 2, 0.39 g of sodium borohydride and 1 ml of ethanolaminewere brought into reaction, followed by after-treatment, whereby 227.8mg of the above-identified compound were obtained, wherein theprocedures were modified such that 0.56 ml (2 eq.) of triethylamine wasused as the basic catalyst and the purification was effected by a columnchromatography (methanol/ethyl acetate of 1/5), with subsequent PTLC(methanol/ethyl acetate of 1/5). Rf=0.28 (methanol/ethyl acetate of1/5).

EXAMPLE 17

[0380](±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamideHydrochloride

[0381] A. Synthesis of 1-(3-formylaminophenyl)ethanone

[0382] To a solution of 2 g of 1-(3-aminophenyl)ethanone (supplied fromTokyo Chemical Industry Co., Ltd.) in 15 ml of dimethylformamide, amixture of 15 ml of formic acid and 5 ml of acetic anhydride was addedand the mixture was agitated for 2.5 hours. Then, the agitation wascontinued for further 15 hours at room temperature and thereto was addeda mixture of 3 ml of formic acid and 1 ml of acetic anhydride andagitation was continued for further 8 hours at room temperature. To thismixture, 150 ml of water and 150 ml of ethyl acetate were added toeffect extraction. The organic layer was rinsed with water twice anddried, whereupon the solvent was distilled off under a reduced pressureto obtain 1.69 g of the-above-identified compound. Rf=0.65(methanol/chloroform of 1/10).

[0383] B. Synthesis of (±)-N-[3-(2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]formamide Hydrochloride

[0384] To a solution of 1.6 g of the above 1-(3-formylaminophenyl)ethanone in 33.4 ml of 1, 4-dioxane, 1.63 g of bromine were added andthe mixture was agitated for 1 hour at 60° C. The mixture wasconcentrated under a reduced pressure, 40 ml of water were added tothe-resulting residue and the mixture was agitated vigorously underice-cooling. To this mixture was added ethyl acetate to effectextraction and the organic layer was dried, before the solvent wasdistilled off under a reduced pressure. To the resulting residue,chloroform and water were added and the deposited precipitate wasseparated by filtration. By distilling off the solvent from the filtrateunder a reduced pressure, 975 mg of a mixture containing2-bromo-1-(3-formylaminophenyl)ethanone were obtained.

[0385] According to the procedures as described in the step D of Example1, 300 mg of the mixture containing the above bromo-product, 363 mg ofHBr-addition salt of Intermediate 2, 239 mg of sodium borohydride and0.6 ml of ethanolamine were brought into reaction, followed byafter-treatment, whereby 73 mg of the above-identified compound wereobtained, wherein, however, a modification was incorporated in such amanner that 0.34 ml (2 eq.) of triethylamine was used as a basiccatalyst and the purification was effected by a PTLC (methanol/ethylacetate of 1/3) with subsequent conversion into hydrochloride salt,followed by removal of impurities by depositing them from methanol/ethylacetate and filtering them off. Rf=0.26 (methanol/ethyl acetate of 1/3).

EXAMPLE 18

[0386](±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)]ethanolHydrochloride

[0387] A. Synthesis of(±)-[2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-nitro-4-(benzyloxy)phenyl]ethanol

[0388] According to the procedures described in the step D of Example 1,a solution of 0.52 g (70% purity) of 2-bromo-1-[3-nitro-4-(benzyloxy)phenyl]ethanone [prepared by the method reported by Carl Kaiser et al inJ. Med. Chem., 17,49-57(1974)] in a mixture of 409 μl of triethylamineand 6.4 ml of anhydrous acetonitrile and a solution of 287 mg of sodiumborohydride in 13 ml of absolute ethanol were added successively to asolution of 435 mg of HBr-addition salt of Intermediate 2 in a mixedsolvent composed of 25.5 ml of anhydrous acetonitrile and 20 ml ofanhydrous dimethylformamide, followed by reaction and after-treatment,whereby 61.8 mg of the above-identified compound were obtained. Rf=0.24(methanol/chloroform of 1/10).

[0389] B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxy-3-nitrophenyl)ethanolHydrochloride

[0390] To a solution of 127.6 mg of the compound of the above step A in10 ml of dichloromethane, 0.69 ml of 1 M solution of boron tribromide indichloromethane (supplied from the firm Aldrich) was added dropwise overa period of 2 minutes under cooling with dry ice/acetone coolant. Themixture was agitated as such for one hour and, then, the agitation wascontinued for further 5 minutes under ice-cooling. The reaction wasterminated by adding 10 ml of methanol to the reaction mixture and theproduct was extracted therefrom with ethyl, acetate after adjusting thereaction mixture at pH of 8.7 using saturated aqueous sodium bicarbonatesolution. The organic layer was rinsed with saturated aqueous sodiumchloride solution and dried, whereupon the solvent was distilled offunder a reduced pressure. The resulting residue was triturated in ethylacetate and the mixture was filtered to obtain 87.6 mg of free baseproduct of the above-identified compound. This was converted intohydrochloride salt which is the above-identified compound by using 0.1 NHCl/ethanol (93.0 mg). Rf=0.33 (methanol/chloroform of 1/10).

EXAMPLE 19

[0391](±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-amino-4-hydroxyphenyl)ethanol2HCl

[0392] 15 mg of the compound of Example 18 were dissolved in a mixedsolvent composed of 1 ml of methanol and 1 ml of tetrahydrofuran inaccordance with the procedures described in the step E of Example 12 andthereto were added 1.1 mg of platinum oxide (anhydrous, supplied fromWako Pure Chem. Co.) under ice-cooling, followed by reaction andafter-treatment, whereby 10.2 mg of the above-identified compound wereobtained. Rf=0.15 (methanol/ethyl acetate of 1/3).

EXAMPLE 20

[0393](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]ureaHydrochloride

[0394] According to the procedures described in the step D of Example 1,a solution of 0.54 g of 2-bromo-1-[4-(benzyloxy)-3-ureidphenyl]ethanone[prepared by the method reported by Carl Kaiser et al in J. Med. Chem.,17, 49-57 (1974)] in a mixture of 409 μl of triethylamine and 6.4 ml ofanhydrous acetonitrile and a solution of 287 mg of sodium borohydride in13 ml of absolute ethanol were added successively to a solution of 435mg of HBr-addition salt of Intermediate 2 in a mixed solvent composed of26 ml of anhydrous acetonitrile and 10 ml of anhydrousdimethylformamide, followed by reaction and after-treatment, whereby59.3 mg of the above-identified compound were obtained. Rf=0.15(methanol/chloroform of 1/10).

EXAMPLE 21

[0395] Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]ureaHydrochloride

[0396] According to the procedures as given in Example 2, the compoundof Example 20 (in a solution of 40 mg of the compound in 5.3 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (25 mg), whereby the above-identified compound (29.8 mg) wasobtained. Rf=0.08 (methanol/chloroform of 1/10).

EXAMPLE 22

[0397] Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]formamideHydrochloride

[0398] According to the procedures described in the step D of Example 1,a solution of 0.52 g of 2-bromo-1-[3-(formylamino)-4-(benzyloxy)phenyl]ethanone [prepared by the method reported by Carl Kaiser et al inJ. Med. Chem. 17, 49-57 (1974)] in a mixture of 409 μl of triethylamineand 10 ml of anhydrous acetonitrile and a solution of 287 mg of sodiumborohydride in 13 ml of absolute ethanol were added successively to asolution of 435 mg of HBr-addition salt of Intermediate 2 in a mixedsolvent composed of 22 ml of anhydrous acetonitrile and 6 ml ofanhydrous dimethylformamide, followed by reaction and after-treatment,whereby 57.0 mg of the above-identified compound were obtained. Rf=0.18(methanol/chloroform of 1/10).

EXAMPLE 23

[0399] Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]formamideHydrochloride

[0400] According to the procedures as given in Example 2, the compoundof Example 22 (in a solution of 40 mg of the compound in 5.8 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (27 mg), whereby the above-identified compound (28.1 mg) wasobtained. Rf=0.08 (methanol/chloroform of 1/10).

EXAMPLE 24

[0401] Synthesis of(±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-dimethylsulfamideHydrochloride

[0402] According to the procedures described in the step D of Example 1,a solution of 0.64 g of2-bromo-1-[4-(benzyloxy)-3-(dimethylsulfamoylamino)phenyl]ethanone[preparedby the method reported by Carl Kaiser et al in J. Med. Chem. 17, 49-57(1974)] in a mixture of 410 μl of triethylamine and 6.5 ml of anhydrousacetonitrile and a solution of 287 mg of sodium borohydride in 15 ml ofabsolute ethanol were added successively to a solution of 435 mg ofHBr-addition salt of Intermediate 2 in a mixed solvent composed of 26 mlof anhydrous acetonitrile and 10 ml of anhydrous dimethylformamide,followed by reaction and after-treatment, whereby 70.5 mg of theabove-identified compound were obtained. Rf=0.17 (methanol/chloroform of1/10).

EXAMPLE 25

[0403] Synthesis of(±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0404] According to the procedures as given in Example 2, the compoundof Example 24 (in a solution of 40 mg of the compound in 5.1 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (24 mg), whereby the above-identified compound (38.3 mg) wasobtained. Rf=0.38 (methanol/ethyl acetate of 1/3).

EXAMPLE 26

[0405] (±)-2-[N-[2-(9H-carbazo 1-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-(benzyloxy)phenyl]ethanol.2HCl

[0406] According to the method reported by Carl Kaiser et al in J. Med.Chem. 17, 49-57 (1974), a solution of 500 mg of the compound of Example22 in 1 ml of tetrahydrofuran was added dropwise to a suspension of 50mg of lithium aluminum hydride in 2 ml of tetrahydrofuran to causereaction, followed by after-treatment, whereby 381 mg of theabove-identified compound were obtained. Rf=0.13 (methanol/chloroform of1/10).

EXAMPLE 27

[0407](±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[3-(methylamino)-4-hydroxyphenyl]ethanol.2HCl

[0408] According to the procedures as given in Example 2, the compoundof Example 26 (in a solution of 200 mg of the compound in 25 ml ofmethanol) was subjected to a hydrogenolysis using 10% palladium/carbonblack (100 mg), whereby the above-identified compound (153 mg) wasobtained. Rf=0.09 (methanol/chloroform of 1/10).

EXAMPLE 28

[0409] (±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-fluorophenyl)ethanol Hydrochloride

[0410] A. Synthesis of (±)-2-fluorostyrene oxide (Intermediate 30)

[0411] To a solution of 5.00 g of 2-fluorostyrene (supplied from thefirm Aldrich) in 200 ml of methylene chloride, 17.7 g ofmetachloroperbenzoic acid (supplied from Kanto Chem. Co. Inc.) and 18.6g of disodium phosphate were added under ice-cooling and the mixture wasagitated at room temperature for 20 hours. The mixture was cooled withice and the thereby deposited crystals were removed by twice filtrationsand the filtered cake was washed with aqueous sodium thiosulfatesolution-(180 ml), whereupon the organic phase was dried and the solventwas distilled off under a reduced pressure, followed by purification bya column chromatography (ethyl acetate/n-hexane of 1/19), whereby 0.38 gof the above-identified compound was obtained. Rf=0.57 (ethylacetate/n-hexane of 1/5).

[0412] B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]-amino]-1-(2-fluorophenyl)ethanolHydrochloride

[0413] Under argon atmosphere, 1.6 ml of dimethyl sulfoxide and 1.06 mlof N,O-bis(trimethylsilyl)acetamide (25% solution in acetonitrile,supplied from Tokyo Chemical Industry Co., Ltd.) were added to 452. 6 mgof Intermediate 2 and the resulting mixture was agitated at roomtemperature for 30 minutes. Thereto were then added 290 mg ofIntermediate 30 and the agitation was continued at 70° C. for 70 hours.

[0414] The reaction mixture was cooled down to room temperature and 2 mlof 6 N hydrochloric acid were added thereto and the mixture was agitatedfor 5 minutes, whereupon the resulting mixture was made basic using 5 Naqueous sodium hydroxide. Then, the mixture was extracted with ethylacetate, whereupon the organic phase was dried and the solvent wasdistilled off under a reduced pressure, followed by purification by acolumn chromatography (chloroform-methanol/chloroform of 3/100-7/100) toobtain a free amine product of the above-identified compound. Rf=0.20(methanol/chloroform of 1/9). Using 0.1 N hydrogen chloride/ethanol, 268mg of the above-identified compound were obtained.

EXAMPLE 29

[0415] (±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyphenyl)ethanol Hydrochloride

[0416] A. Synthesis of 2-bromo-1-(4-benzyloxy)phenylethanone(Intermediate 31)

[0417] Under argon atmosphere, 7.4 g of copper(II) bromide weresuspended in 100 ml of ethyl acetate and thereto was added a solution of5 g of 1-(4-benzyloxy)-phenylethanone (supplied from the firmTransworld) in 100 ml of chloroform with agitation while heating underreflux. After agitation for 5.5 hours, the mixture was cooled down to62° C. and was diluted with 100 ml of chloroform, followed by,filtration of the suspension and evaporation under a reduced pressure.The resulting residue was suspended in isopropyl alcohol and precipitatewas removed by filtration, followed by rinsing with cold isopropylalcohol and drying, whereby 4.52 g of the above-identified compound wereobtained as pale yellow crystals.

[0418] B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-(benzyloxy)phenyl]ethanol(Intermediate 32)

[0419] 400 mg of Intermediate 31 and 534 mg of Intermediate 2 weresubjected to reaction and after-treatment in accordance with theprocedures of the step D of Example 1, whereby 120 mg of theabove-identified compound were obtained. Here, however, the crudeproduct was purified by a column chromatography (ethyl acetate/methanolof 8/1).

[0420] C. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(4-hydroxyoxyphenyl)ethanol

[0421] 120 mg of Intermediate 32 were dissolved in 15 ml ofdimethylformamide, whereto were added 100 μl of acetic acid and, then,120 mg of 10% palladium/carbon black rinsed with 2 ml ofdimethylformamide, whereupon the mixture was subjected to ahydrogenolysis under 1 atm for 50 minutes. After-treatments wereeffected in accordance with the procedures of Example 2, whereby 88 mgof the above-identified compound were obtained. Rf=0.31 (methanol/ethylacetate of 1/3).

EXAMPLE 30

[0422] (±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanol Hydrochloride

[0423] A. Synthesis of 2-bromo-1-(2-benzyloxy)phenylethanone

[0424] Under argon atmosphere, 14.6 g of copper (II) bromide weresuspended in 175 ml of ethyl acetate and thereto was added a solution of6.35 g of 1-(4-benzyloxy)phenylethanone (supplied from the firmTransworld) in 175 ml of chloroform with agitation while heating underreflux. By after-treatment in accordance with the procedures of the stepA of Example 29, a fraction containing the above-identified compound(9.32 g) was obtained, which was served for the subsequent reaction assuch without further treatment.

[0425] B. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[2-(benzyloxy)phenyl]ethanol(Intermediate 33) 442 mg of the above-obtained compound and 400 mg ofIntermediate 2 were subjected to reaction and after-treatment inaccordance with the procedures of the step D of Example 1, whereby 31.9mg of the above-identified compound were obtained. Here, however, thecrude product was purified by a column chromatography(methanol/chloroform of 1/20).

[0426] D. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(2-hydroxyphenyl)ethanolAcetic Acid Addition Salt

[0427] 31.9 mg of Intermediate 33 were dissolved in 4.7 ml of methanoland thereto were added 4 Al of acetic acid and the mixture was subjectedto a hydrogenolysis under 1 atm hydrogen gas using 22.3 mg of 10%palladium/carbon black (room temperature, 5 hours). The catalyst wasfiltered off on celite and was washed with chloroform and methanol. Thefiltrate and the washed liquor were brought together, from which thesolvent was distilled off under a reduced pressure, whereby 18.5 mg ofthe above-identified compound were obtained as a powdery product.Rf=0.13 (methanol/chloroform of 1/10).

EXAMPLE 31

[0428] (±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanolHydrochloride

[0429] To a solution of 140 mg of HBr addition salt of Intermediate 2and 110 μl of triethylamine in 5 ml of methanol, 92.0 mg ofphenylglyoxal were added and the mixture was heated on a water bath for4 minutes. After cooling, 120 mg of sodium borohydride were addedthereto in two portions at an interval of 10 minutes and the mixture wasagitated at room temperature for 20 hours. The solvent was distilled offunder a reduced pressure and thereto were added ethyl acetate and waterto cause liquid separation, whereupon the organic solvent was dried andevaporated off under a reduced pressure. The resulting residue waspurified by a column chromatography (methanol/chloroform of 1/25),whereby 116.3 mg of the above-identified compound were obtained. Byrecrystallization from ethanol, 93.8 mg were obtained as hydrochloricacid addition salt. Rf=0.34 (methanol/chloroform of 1/10).

EXAMPLE 32

[0430] (R)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenyl]ethanolHydrochloride

[0431] To 200 mg of Intermediate 2, 0.5 ml of dimethylsulfoxide and 102μl of (R)-(±)-styrene oxide (supplied from the firm Aldrich) were addedand the resulting mixture was agitated at 70° C. for 70 hours. Themixture was made basic with addition of water and sodium hydrogencarbonate and was then subjected to extraction with ethyl acetate,followed by drying of the organic layer, whereupon the solvent wasdistilled off under a reduced pressure and the resulting residue waspurified by a column chromatography (methanol/chloroform of 1/20) toobtain 93.4 mg of the above-identified compound. Rf=0.34(methanol/chloroform of 1/10).

[0432] The optical purity was found to be such that it is constituted ofnearly 100% of (R)-modification after high performance liquidchromatography using CHIRALCEL OD-R (4.6 mmø×25 cm, of Daicel Chem.Ind.). The analysis was carried out with a mobile phase of 0.5 MNaClO₄/CH₃CN of 1/1, a flow rate of 0.5 ml/min., a detection wave lengthof 254 nm, a column temperature of 25° C. with retention time of 33.2min. for (R)-modification and 32.4 min. for (S)-modificationrespectively. Using an ethanolic hydrogen chloride solution, 70 mg ofhydrochloric acid addition salt were obtained.

EXAMPLE 33

[0433] (S)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-phenylethanolHydrochloride

[0434] To 70.4 mg of Intermediate 2, 0.3 ml of dimethyl sulfoxide and 36A I of (S)-(−)-styrene oxide (supplied from the firm Aldrich) were addedand the resulting mixture was agitated at 70° C. for 70 hours. Themixture was made basic with addition of water and sodium hydrogencarbonate and was then subjected to extraction with ethyl acetate,followed by drying of the organic layer, whereupon the solvent wasdistilled off under a reduced pressure and the resulting residue waspurified by a PTLC (chloroform/methanol of 10/1) to obtain 22.4 mg ofthe above-identified compound. Rf=0.34 (methanol/chloroform of 1/10).The optical purity was found, after high performance liquidchromatography as in Example 32 with the analysis under the samecondition, to be such that it is constituted of nearly 100% of(S)-modification and the retention time was found to be 32.4 min. Byusing an ethanolic hydrogen chloride solution. 15 mg of hydrochloricacid addition salt were obtained.

EXAMPLE 34

[0435] (±)-2-[N-[2-(dibenzofuran-2-yloxy)ethyl]amino]-1-phenylethanolHydrochloride

[0436] To a solution of 105 mg of HBr-addition salt of Intermediate 2and 110 μl of triethylamine in 5 ml of methanol, 69 mg of phenylglyoxalwere added, followed by procedures in accordance with those of thesynthesis method in Example 31, whereby 63.6 mg of the above-identifiedcompound were obtained. Rf=0.48 (methanol/chloroform of 1/10). Using anethanolic solution of hydrogen chloride, 40 mg of hydrochloride saltwere obtained.

EXAMPLE 35

[0437](R,R)-2-[N-[1-(9H-carbazol-2-yloxy)propan-2-yl]amino]-1-phenylmethanolHydrochloride

[0438] To 597 mg of2-(N-tert-butoxycarbonylamino-1-propyloxy)-9H-carbazole synthesizedaccording to the procedures of Example 11, 10 ml of 30% solution ofhydrogen bromide in acetic acid were added and the reaction and theafter-treatments were carried out in accordance with the procedures ofthe synthesis of Example 32, whereby 258 mg of the above-identifiedcompound were obtained. Rf=0.47 (methanol/chloroform of 1/9). Theoptical purity was found by an analysis performed under the samecondition as in Example 32 except that it was carried out using a highperformance liquid chromatography at 30° C. to be such that the productwas constituted of nearly 100% in the form of (R, R)-modification. Theretention time was 27.3 minutes. The product was converted intohydrochloric acid addition salt by using 6 NM hydrochloric acid (280mg).

EXAMPLE 36

[0439](±)-2-[N-[2-[(9H-3-aminocarbazol)-2-yloxy]ethyl]amino]-1-phenylethanol.

2HCl

[0440] A. Synthesis of N-[2-(9H-carbazol-2-yloxy)ethyl]acetamide(Intermediate 34)

[0441] To a solution of 1 g of Intermediate 2 and 0.93 ml oftriethylamine (supplied from Wako Pure Chemical Ind., Ltd.) in 5 ml ofdichloromethane, solution of 0.4 ml of acetyl chloride (supplied fromWako Pure Chemical Ind.) in 2 ml of dichloromethane were added underice-cooling and agitation. The mixture was agitated for 2.5 hours underice-cooling and, then, warmed to room temperature. Thereto were addedethyl acetate and water and the organic layer was separated, which waswashed with aqueous saturated aqueous sodium chloride solution anddried, whereupon the solvent was distilled off under a reduced pressure.The resulting product was dried at room temperature under a reducedpressure, whereby 1.16 g of the above-identified compound were obtained.Rf=0.47 (methanol/chloroform of 1/9).

[0442] B. Synthesis of N-[2-[(9H-3-nitrocarbazol)-2-yloxy]ethyl]acetamide (Intermediate 35)

[0443] To a solution of 500 mg of Intermediate 34 in 20 ml of aceticacid, 0.4 ml of 20% nitric acid at 60° C. under agitation. After 1minute, 20 ml of ice water were added thereto and the mixture wasagitated, whereupon water was further added thereto, followed byextraction with ethyl acetate. Organic layer was washed with water,adjusted at pH 8 with 5 N aqueous sodium hydroxide solution and washedwith saturated aqueous sodium chloride solution. After drying, thesolvent was distilled off under a reduced pressure and the resultingresidue was purified by a column chromatography (methanol/chloroform of1/50), whereby 271.2 mg of the above-identified compound were obtained.Rf=0.50 (twice developments with methanol/chloroform of 1/9).

[0444] C. Synthesis of N-2-[(9H-3-nitrocarbazol)-2-yloxy]ethyl] amine(Intermediate 36)

[0445] 100 mg of Intermediate 35 were suspended in 2.5 N hydrochloricacid and the mixture was agitated at room temperature for 10 days and,then, agitation was further continued at 100° C. for 4 hours. To thismixture was added ethyl acetate and pH thereof was adjusted at 10 using5 N aqueous sodium hydroxide to perform extraction. After drying, thesolvent was distilled off under a reduced pressure, whereby 71.2 mg ofthe above-identified compound were obtained. Rf=0.11 (thricedevelopments with methanol/chloroform of 1/10).

[0446] D. Synthesis of(t)-2-[N-[2-[9H-3-nitrocarbazol)-2-yloxy]ethyl]amino]-1-phenylethanolHydrochloride (Intermediate 37)

[0447] 71.2 mg of Intermediate 36. 52,8 mg of phenylglyoxal (suppliedfrom Tokyo Chemical Industry Co., Ltd.) and 54.8 μl of triethylaminewere dissolved in 5 ml of methanol and the mixture was agitated at 70°C. for 4 minutes. The mixture was then cooled with ice and thereto wereadded 79 mg of sodium borohydride under agitation. Agitation wascontinued for further 21 hours, while the temperature was allowed torise gradually to room temperature. Ethyl acetate and water were addedthereto and the mixture was agitated for 15 minutes, whereupon theorganic layer was separated and dried and the solvent was distilled offunder a reduced pressure. The resulting residue (112.1 mg) was purifiedby a column chromatography (methanol/chloroform of 1/25), whereby 17.1mg of the above-identified compound were obtained. Rf=0.34(methanol/chloroform of 1/10).

[0448] E. Synthesis of(±)-2-[N-[2-[(9H-3-aminocarbazol)-2-yloxy]ethyl]amino]-1-phenylethanol.2HCl

[0449] To a solution of 71.8 mg of the compound of Intermediate 37 in3.7 ml of methanol, 0.16 ml of concentrate hydrochloric acid and 68.6 mgof iron powder (supplied from Kanto Chemical Co., Inc.) were added,successively, and the mixture was agitated at room temperature for 3.5hours and, then, agitation was continued at 40° C. for additional 5minutes. The mixture was adjusted at pH 9 using water and 5 N aqueoussodium hydroxide solution, followed by extraction with ethyl acetate anddrying, whereupon the solvent was distilled off under a reducedpressure. To the resulting residue were added 4 ml of 0.1 N hydrogenchloride/ethanol and the solvent was distilled off under a reducedpressure, whereupon recrystallization from ethanol/ethyl acetate wasincorporated. The crystals were isolated by filtration and were washedwith ethyl acetate and diethyl ether, successively, with subsequentdrying under a reduced pressure, whereby 29 mg of the above-identifiedcompound were obtained. Rf=0.14 (free compound, methanol/chloroform of1/10).

EXAMPLE 37

[0450](±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamideHydrochloride

[0451] A. Synthesis of 3-(2-benzyloxycarbonylaminoethoxy)dibenzothiophene (Intermediate 38)

[0452] To a solution of 370.6 mg of 3-hydroxydibenzothiophene [preparedby the method reported by H. Kudo in J. Heterocycl. Chem., 22 (1),215-218 (1985)] and 768 mg of potassium carbonate in 4 ml ofdimethylformamide, 720 mg of Intermediate 0 were added and the mixturewas heated at 60° C. for 30 hours. Thereto were added ethyl acetate andwater to effect extraction, whereupon the organic layer was dried andthe solvent was distilled off under a reduced pressure to thereby obtain637 mg of the above-identified compound after purification by a columnchromatography (methanol/chloroform of 1/100). Rf=0.17 (ethylacetate/n-hexane of 1/5).

[0453] B. Synthesis of 2-(dibenzothiophen-3-yloxy)ethylamine(Intermediate 39)

[0454] To 637 mg of Intermediate 38, 12 ml of 30% solution of hydrogenbromide in acetic acid were added and the mixture was agitated at roomtemperature for 2.5 hours. Thereto was added diethyl ether underice-cooling and the thereby deposited precipitate was filtered off.After adjusting the pH of the remainder to 10 by adding water and NaOH,extraction with ethyl acetate was incorporated and the organic layer wasdried, before the solvent was distilled off under a reduced pressure,whereby 334.2 mg of the above-identified compound were obtained. Rf=0.10(methanol/chloroform of 1/10).

[0455] C. Synthesis of (±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamideHydrochloride

[0456] To a solution of 334.2 mg of Intermediate 39 in 14 ml ofanhydrous acetonitrile, a solution of 980 mg of Intermediate 3 (70%purity) in 7 ml of anhydrous acetonitrile and 210 Al of triethylaminewere added under argon atmosphere at 0° C., whereupon the reactionmixture was removed from the ice bath and was agitated for 83 minutes.Thereto was then added a solution of 270 mg of sodium borohyride in 14ml of absolute ethanol at room temperature. After agitation for 6.5hours, the reaction was terminated using 1.0 N hydrochloric acid (pH 4)and thereto was added 0.7 g of ethanolamine. After agitation for 10minutes, the mixture was diluted with ethyl acetate, organic layer wasrinsed with saturated aqueous sodium chloride solution and dried and thesolvent was distilled off under a reduced pressure, whereby 1.09 g ofcrude product were obtained. This was purified by a columnchromatography (methanol/chloroform of 3/100), whereby 240.6 mg of freeamine product of the above-identified compound were obtained. Rf=0.38(methanol/chloroform of 1/10). To a part (46 mg) of the so-obtainedproduct, 1.1 equivalent amount of 0.1 N hydrogenchloride/ethanol wereadded to convert it into hydrochloride salt (the above-identifiedcompound), whereupon the solvent was distilled off under a reducedpressure. To the resulting residue, diethyl ether was added and thethereby deposited precipitate was filtered off, whereupon the filtratewas rinsed with diethyl ether and dried under a reduced pressure at 50°C., whereby 48.5 mg of the above-identified compound were obtained.

EXAMPLE 38

[0457](±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0458] 43 mg of the compound of Example 37 were subjected to ahydrogenolysis under 1 atm hydrogen gas using 30 mg of 10%palladium/carbon black (supplied from the firm Merck) and 5 ml ofmethanol. The catalyst was filtered off and washed with chloroform,methanol and hot methanol, successively. The filtrate and the washedliquor were brought together, from which the solvent was distilled offunder a reduced pressure, whereby 32.5 mg of the above-identifiedcompound were obtained as a white powdery product. Rf=0.08(methanol/chloroform of 1/10).

EXAMPLE 39

[0459](±)-N′-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0460] A. Synthesis of 2-bromo-1-[4-benzyloxy-3-[(dimethylsulfamoyl)amino]phenyl]ethanone (Intermediate 40)

[0461] In the same manner as in the case of Intermediate 3, the abovewas prepared from 4-hydroxyacetophenone (supplied from Tokyo ChemicalIndustry Co., Ltd.) in four process steps [by the method reported by A.A. Larsen et al in J. Med. Chem., 10, 462-472 (1967)], wherein however,bromination was effected in the same manner as the procedures given inthe step A of Example 29. Rf=0.37 (chloroform).

[0462] B. Synthesis of (±)-N′-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0463] To a solution of 462 mg of Intermediate 39 in 20 ml of anhydrousacetonitrile, a solution of 470 mg of Intermediate 40 in 10 ml ofanhydrous acetonitrile was added under argon atmosphere at 0° C.,whereupon the reaction mixture was removed from the ice bath and wasagitated for 110 minutes. Thereto was then added a solution of 215 mg ofsodium borohydride in 20 ml of absolute ethanol at room temperature.After agitation for 70 minutes, the reaction was terminated using 1 Nhydrochloric acid (pH 4) and the thereto was added 0.54 g ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith ethyl acetate, organic layer was rinsed with saturated aqueoussodium chloride solution and dried, whereupon it was evaporated under areduced pressure, whereby a crude product was obtained. This waspurified by a column chromatography (methanol/chloroform of 3/100),whereby 200.2 mg of free amine product of the above-identified compoundwere obtained. Rf=0.37 (methanol/chloroform of 1/10). The procedures ofadding thereto 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanolto convert it into hydrochloride salt (the above-identified compound),distilling off of the solvent under a reduced pressure, adding to theresulting residue dimethyl ether and filtering off the thereby depositedprecipitate were repeated twice, followed by drying under a reducedpressure, whereby 210.8 mg of the above-identified compound wereobtained.

EXAMPLE 40

[0464](±)-N′-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0465] 210.8 mg of the compound of Example 39 were subjected to ahydrogenolysis under 1 atm hydrogen gas using 107 mg of 10%palladium/carbon black and 22.5 ml of methanol. The catalyst wasfiltered off and washed with hot methanol. The filtrate and the washedliquor were brought together, from which the solvent was distilled offunder a reduced pressure, whereby 137.9 mg of the above-identifiedcompound were obtained. Rf=0.26 (methanol/chloroform of 1/10).

EXAMPLE 41

[0466](±)-N-[3-[2-[2-(dibenzothiophen-3-yloxy)ethtlamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0467] To a solution of 462 mg of Intermediate 39 in 20 ml of anhydrousacetonitrile, a solution of 320.2 mg of Intermediate 14 in 10 ml ofanhydrous acetonitrile was added under argon atmosphere at 0° C.,whereupon the reaction mixture was removed from the ice bath and wasagitated for 115 minutes. To this mixture was then added a solution of215 mg of sodium borohydride in 20 ml of absolute ethanol at roomtemperature. After agitation for 75 minutes, the reaction was terminatedusing 1 N hydrochloric acid (pH 4) and thereto was added 0.54 g ofethanolamine. After agitation for 10 minutes, the mixture was dilutedwith ethyl acetate, organic layer was rinsed with saturated aqueoussodium chloride solution and dried, whereupon it was evaporated under areduced pressure. This was purified by a column chromatography (elutionby methanol/ethyl acetate of 1/7), whereby 251.3 mg of fractionscontaining the free amine product of the above-identified compound wereobtained. This was further purified by a PTLC (elution withmethanol/ethyl acetate of 1/7), whereby 134.7 mg of free amine productof the above-identified compound were obtained. Rf=0.50 (methanol/ethylacetate of 1/7). To this, 1.1 equivalent amount of 0.1 N hydrogenchloride/ethanol were added to convert it into hydrochloride salt (theabove-identified compound), which was washed with ethanol, ethyl acetateand diethyl ether, successively, with subsequent drying under a reducedpressure, whereby 93.9 mg of the above-identified compound wereobtained.

EXAMPLE 42

[0468](±)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide

[0469] A. Synthesis of(±)-N-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxyphenyl]-N.N-dimethylsulfamide (intermediate 41)

[0470] To a solution of 15.1 g Intermediate 40 in 197 ml of anhydroustetrahydrofuran under ice-cooling, a solution of 61.9 ml of 1 Mborane/tetrahydrofuran complex in tetrahydrofuran (supplied from thefirm Aldrich) were added all at once and the mixture was agitated atthis temperature for 75 minutes. The mixture was then diluted with 500ml of ethyl acetate and thereto was added saturated aqueous ammoniumchloride solution in small portions to wash the organic layer twice. Theorganic layer was separated and was washed with saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate, whereupon thesolvent was distilled off under a reduced pressure. The residue wasfurther dried under a reduced pressure overnight using a vacuum pump,whereby 14.91 g of the above-identified compound were obtained.Rf=0.27(ethyl acetate/n-hexane of 1/2).

[0471] B. Synthesis of (±)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide (Intermediate 42)

[0472] To a solution of 14.9 g of Intermediate 41 in 212.9 ml ofacetone, 58.09 g of sodium iodide were added and the mixture was heatedunder reflux for 105 minutes. The mixture was then cooled down to roomtemperature and was filtered, before the solvent was distilled off undera reduced pressure. The resulting residue was subjected to a phasepartition between 214 ml of dichloromethane and 240 ml of water and theorganic layer was washed twice with 23.5% by weight aqueous sodiumhydrogen sulfide solution and, then, with saturated aqueous sodiumchloride solution, before it was dried and the solvent was distilled offunder a reduced pressure. This was further dried under a reducedpressure for two hours by a vacuum pump, whereby 15.51 g of browntar-like product (iodo-isomer) were obtained. This was dissolved in 75.6ml of dimethylformamide and thereto were added 6.1 g of imidazole and346 mg of 4-dimethylaminopyridine, followed by a further addition of5.83 ml of chlorotriethylsilane. After agitation for 35 minutes, themixture was diluted with 250 ml of ethyl acetate and 100 ml of n-heptaneand, then, washed with water (125 ml), with a saturated copper sulfatesolution (twice, 125 ml), with water (125 ml) and, finally, with asaturated aqueous sodium chloride solution (125 ml), successively,followed by drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was purified by a silica gelcolumn chromatography and the target compound was obtained (15.41 g)from n-hexane-eluted fractions as a slightly brownish solid. Rf=0.86(ethyl acetate/n-hexane of 1/1).

[0473] C. Synthesis of (±)-N′-[5-[2-[2-(dibenzofuran:-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 43)

[0474] A solution of 150 mg of Intermediate 42, 71.6 mg of Intermediate5 and 0.44 ml of Hunig Base (supplied from the firm Aldrich) in 0.5 mlof dimethylacetamide was agitated at 60° C. for 12 hours. To thereaction mixture, 40 ml of ethyl acetate and 40 ml of water were addedto effect extraction and the aqueous phase was further extracted withethyl acetate three times. The united organic phase was dried and thesolvent was distilled off under a reduced pressure. The resultingresidue was purified by a column chromatography(chloroform−methanol/chloroform=1/49), whereby 173 mg of theabove-identified compound were obtained. Rf=0.74 (methanol/chloroform of1/10).

[0475] D. Synthesis of (1)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide

[0476] To a solution of 60.1 mg of Intermediate 43 in 2.9 ml ofanhydrous tetrahydrofuran, 36.8 μl of acetic acid and 574 A l of 1 Msolution of tetrabutyl ammonium fluoride in tetrahydrofuran were addedand the mixture was agitated at room temperature for 1 hour. Thereaction mixture was diluted with ethyl acetate and was washed withsaturated aqueous sodium bicarbonate solution and then with saturatedaqueous sodium chloride solution, followed by drying, whereupon thesolvent was distilled off under a reduced pressure. The resultingresidue was purified by a silica gel chromatography, whereupon theabove-identified compound (50.0 mg) was obtained from eluted fractionswith methanol/chloroform (7/100). Rf=0.39 (methanol/chloroform of 1/10).

EXAMPLE 43

[0477](1)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0478] The compound of Example 42 was dissolved in 5.9 ml of methanoland thereto were added 0.92 ml of 0.1 N hydrogen chloride/ethanol and27.6 mg of 10% palladium/carbon black and the mixture was agitated under1 atm hydrogen gas for 2.5 hours. The catalyst was filtered and washedwith hot methanol, whereupon the solvent was distilled off under areduced pressure. The residue was triturated with diethyl ether and wascollect by filtration. By drying at 50° C. under a reduced pressure for2 hours, the above-identified compound (24.7 mg) was obtained as aslightly brownish amorphous product. Rf=0.25 (methanol/chloroform of1/10).

EXAMPLE 44

[0479](±)-N′-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide

[0480] A. Synthesis of(±)-N′-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 44)

[0481] In the same manner as in the case of Intermediate 43 in the stepC of Example 42, a solution of 486 mg of Intermediate 42. 290.4 mg ofIntermediate 17 and 1.44 ml of Hunig Base (supplied from the firmAldrich) in 1.3 ml of dimethylacetamide was agitated at 60° C. for 16hours. To the reaction mixture, ethyl acetate and water were added toeffect extraction and the aqueous phase was further extracted with ethylacetate three times. The united organic phase was dried and the solventwas distilled off under a reduced pressure. The resulting residue waspurified by a column chromatography(chloroform−methanol/chloroform=1/49), whereby 75.3 mg of theabove-identified compound were obtained. Rf=0.51 (methanol/chloroform of1/10).

[0482] B. Synthesis of(±)-N′-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]2-benzyloxyphenyl]-N,N-dimethylsulfamide

[0483] To a solution of 75.3 mg of Intermediate 44 in 3.3 ml ofanhydrous tetrahydrofuran, 43 μl of acetic acid and 667 μl of 1 Msolution of tetrabutyl ammonium fluoride in tetrahydrofuran were addedand the mixture was agitated at room temperature for 1 hour. Thereaction mixture was diluted with ethyl acetate and was washed withsaturated aqueous sodium bicarbonate solution and then with saturatedaqueous sodium chloride solution, followed by drying over anhydroussodium sulfate, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was triturated with ethanol, whereuponthe above-identified compound (47.1 mg) was obtained as a white powderyproduct. Rf=0.25 (methanol/chloroform of 1/10).

EXAMPLE 45

[0484](±)-N′-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0485] The compound of Example 44 was dissolved in 4.8 ml of methanoland thereto were added 0.78 ml of 0.1 N hydrogen chloride/ethanol and 25mg of 10% palladium/carbon black and the mixture was agitated under 1atm hydrogen gas for 2.2 hours. The catalyst was filtered and washedwith hot methanol, whereupon the solvent was distilled off under areduced pressure. The residue was triturated with diethyl ether and wascollected by filtration. By drying at 50° C. under a reduced pressurefor 2 hours, the above-identified compound (40.6 mg) was obtained as aslightly brownish powdery product. Rf=0.05 (methanol/chloroform of1/10).

EXAMPLE 46

[0486](±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-nitrophenyl)]ethanolHydrochloride

[0487] To a mixed solution of 678.6 mg of HBr addition salt ofIntermediate 2 and 371 μl of triethylamine in 45 ml of anhydrousacetonitrile and 4.5 ml of anhydrous dimethylformamide, a solution of539 mg of 2-bromo-1-(3-nitrophenyl)ethanone [prepared by the methodreported by A. A. Larsen et al in J. Med. Chem. 9, 88-97 (1966)] in 20ml of anhydrous acetonitrile were added under argon atmosphere at 0° C.and the mixture was agitated for 1 hour. This mixture was warmed to theroom temperature (ca. 22° C.) and agitation was continued for further 2hours. To this mixture, a solution of 434 mg of sodium borohydride in 20ml of absolute ethanol was added at room temperature. After agitationfor 1 hour, the reaction was terminated with 1.0 N hydrochloric acid (pH4), whereupon 1.1 ml of ethanolamine were added thereto. After agitationfor 10 minutes, the mixture was diluted with ethyl acetate and theorganic layer was washed thrice with saturated aqueous sodium chloridesolution and dried, whereupon the solvent was distilled off under areduced pressure to obtain 0.93 g of crude product. By recrystallizationfrom ethyl acetate/ethanol, unreacted starting amine compound wasremoved and the filtrate was concentrated, whereupon the resultingresidue was purified by a PTLC (development with methanol/chloroform of1/10), whereby 77.4 mg of free amine compound were obtained. Rf=0.32(methanol/chloroform of 1/10).

[0488] By adding thereto 0.1 N hydrogen chloride/ethanol (1.1 equivalentamount), it was converted into hydrochloride salt (the above-identifiedcompound), followed by evaporating off of the solvent under a reducedpressure. Diethyl ether was added to the resulting residue and thedeposited precipitate was subjected to recrystallization from ethanol,followed by drying at 50° C. under a reduced pressure, whereby theabove-identified compound was obtained as a powdery product.

EXAMPLE 47

[0489](±)2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-(3-aminophenyl)]ethanolHydrochloride

[0490] To a solution of 43.9 mg of the compound of Example 46 in 2 ml ofmethanol, 38.3 mg of iron powder and 90 μl of concentrated hydrochloricacid were added and the mixture was agitated at room temperature for 4hours. The reaction mixture was diluted with water and the pH thereofwas adjusted with 5 N NaOH at 10, whereupon extraction with ethylacetate was carried out. After drying the organic layer, the solvent wasdistilled off under a reduced pressure, whereby 50 mg of a crude productwere obtained. This was purified by a PTLC (development withmethanol/ethyl acetate of 1/4), whereby 16 mg of free amine compoundwere obtained. Rf=0.30 (methanol/ethyl acetate of 1/4).

[0491] This was converted into hydrochloride salt (the above-identifiedcompound) by adding 0.1 N hydrogen chloride/ethanol (1.1 equivalentamount) and the solvent was distilled off under a reduced pressure. Tothe resulting residue, diethyl ether was added and the depositedprecipitate was recrystallized from ethanol, followed by drying at 50°C. under a reduced pressure, whereupon the above-identified compound wasobtained as a powdery product.

EXAMPLE 48

[0492](±)-N′-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]-N,N-dimethylsulfamideHydrochloride

[0493] The reaction and the after-treatments were followed as in Example46 except that 710 mg of2-brom-1-[3-[(dimethylsulfamoyl)amino]phenyl]ethanone [prepared by themethod reported by A. A. Larsen et al in J. Med. Chem., 9, 88-97 (1966)]were employed and the resulting residue was purified by a PTLC(development with methanol/ethyl acetate of 1/4), whereby 112.2 mg offree amine compound were obtained. Rf=0.52 (methanol/ethyl acetate of1/3).

[0494] This was converted into hydrochloride salt (the above-identifiedcompound) by adding 0.1 N hydrogen chloride/ethanol (1.1 equivalentamount) and the solvent was distilled off under a reduced pressure. Tothe resulting residue, diethyl ether was added and the depositedprecipitate was recrystallized from ethanol, followed by drying at 50°C. under a reduced pressure, wherupon the above-identified compound(93.2 mg) was obtained as a powdery product.

EXAMPLE 49

[0495](±)-N-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamideHydrochloride

[0496] According to the procedures described in Example 1, 500 mg ofIntermediate 17 and 1.06 g of Intermediate 3 (70% purity) were subjectedto coupling reaction and the resulting product was then subjected toreduction using 359 mg of sodium borohydride, whereupon the reactionmixture was purified by a silicagel column chromatography(methanol/chloroform of l/9), to obtain 245 mg of free amine product ofthe above-identified compound. Rf=0.24 (methanol/chloroform of 1/10). Apart (97 mg) of it was converted into hydrochloride salt (100 mg) with0.1 N hydrogen chloride/ethanol.

EXAMPLE 50

[0497](±)-N-[5-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0498] According to the procedures described in Example 2, the compoundof Example 49 (100 mg) was dissolved in 10.5 ml of methanol andsubjected to a hydrogenolysis using 49.5 mg of 10% -palladium/carbonblack. The catalyst was filtered on celite at room temperature andwashed with hot methanol. After the filtrate and the washed liquor werebrought together, the solvent was distilled off under a reducedpressure, whereby above-identified compound (77.5 mg) was obtained.Rf=0.03 (methanol/chloroform of 1/10).

EXAMPLE 51

[0499](±)-N-[5-[2-[2-(9H-7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]methanesulfonamideHydrochloride

[0500] 72.1 mg of the free amine compound of Example 49 were dissolvedin 10 ml of 10% solution of hydrogen chloride/methanol and was agitatedat room temperature for 41 hours. The deposited precipitate was filteredoff and washed with diethyl ether, followed by drying (40 minutes) undera reduced pressure at 50° C. to obtain the above-identified compund (49mg). Rf=0.27 (methanol/chloroform of 1/10).

EXAMPLE 52

[0501](±)-N-[5-[2-[2-(9H-7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0502] According to the procedures described in Example 2, the compoundof Example 51 (49 mg) was dissolved in 5.4 ml of methanol and subjectedto a hydrogenolysis using 10% Pd-C (25.9 mg). The catalyst was filteredon celite at room temperature and washed with hot methanol. After thefiltrate and the washed liquor were brought together, the solvent wasdistilled off under a reduced pressure, whereby the the above-identifiedcompound (43.1 mg) was obtained. Rf=0.22 (methanol/ethyl acetate of1/3).

[0503](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-2-propanesulfonamideHydrochloride

[0504] A. Synthesis of2-bromo-1-[4-benzyloxy-3-[(isopropyl-sulfonyl)amino]phenyl]ethanone(Intermediate 45)

[0505] The above-identified Intermediate was produced (2.03 g, ca. 70%purity) in two process steps from 1-(3-amino-4-benzyloxyphenyl) ethanone(2 g) in the same manner as in the case of Intermediate 3 (though,bromination was performed according to the method described in the stepA of Example 29) except that isopropylsulfonyl chloride was employedinstead of methanesulfonyl chloride. Rf=0.19 (chloroform).

[0506] B. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-2-propanesulfonamideHydrochloride

[0507] According to the procedures described in Example 1, 1.43 g ofIntermediate 45 (70% purity) and 686 mg of Intermediate 2 were weresubjected to coupling reaction and, subsequently to reduction using 650mg of sodium borohydride, whereupon the reaction mixture was purified bya silica gel chromatography (methanol/chroroform of 11/89), to obtain369 mg of free amine product of the above-identified compound. Rf=0.49(methanol/chroroform of 1/5). This was converted into hydrochloride saltwith 0.1 N hydrogen chloride/ethanol.

EXAMPLE 54

[0508](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-2-propanesulfonamideHydrochloride

[0509] According to the procedures described in Example 2, the compoundof Example 53 (369 mg) was dissolved in 39.9 ml of methanol andsubjected to a hydrogenolysis using 10% Pd-C (190 mg). The catalyst wasfiltered on celite at room temperature and washed with hot methanol.After the filtrate and the washed liquor were brought together, thesolvent was distilled off under a reduced pressure, whereby theabove-identified compound (267 mg) was obtained. Rf=0.27(methanol/ethylacetate of 1/3).

EXAMPLE 55

[0510](±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0511] A. Synthesis of(±)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-fluorophenyl]methanesufonamide(Intermediate 46)

[0512] The reaction and after-treatment were performed in accordancewith the procedures described in the steps A and B of Example 42,whereby the above-identified compound (10.22 g) was obtained fromIntermediate 9 (7.48 g). Rf=0.36 (ethyl acetate/n-hexane of 1/3).

[0513] B. Synthesis of(±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)-ethylamino]-1-(triethylsilyloxy)ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 47)

[0514] The reaction and after-treatment were performed in accordancewith the procedures described in the step C of Example 42, whereby theabove-identified compound (648 mg) was obtained from Intermediate 46(819 mg) and Intermediate 5 (500 mg). Rf=0.44 (methanol/chloroform of1/10).

[0515] C. Synthesis of (±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0516] To a solution of 648 mg of Intermediate 47 in 30 ml oftetrahydrofuran, 2.15 ml of 4 N solution of hydrogen chloride/dioxanewere added and the mixture was agitated at room temperature for 1 hour,whereupon 30 ml of diethyl ether were added thereto and the crystalswere collected by filtration and dried under a reduced pressure toobtain 408.8 mg of the above-identified compound. Rf=0.61(methanol/ethyl acetate of 1/3).

EXAMPLE 56

[0517](±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0518] A. Synthesis of (±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 48)

[0519] The reaction and after-treatment were performed in accordancewith the procedures described in the step C of Example 42, whereby theabove-identified compound (581.8 mg) was obtained from Intermediate 46(811 mg) and Intermediate 39 (500 mg). Rf=0.52 (methanol/chloroform of1/10).

[0520] B. Synthesis of (±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0521] To a solution of 581.8 mg of Intermediate 48 in 30 ml oftetrahydrofuran, 1.88 ml of 4 N solution of hydrogen chloride/dioxanewere added and the mixture was agitated at room temperature for 1 hour,whereupon 30 ml of diethyl ether were added thereto and the crystalswere collected by filtration and dried under a reduced pressure toobtain 412 mg of the above-identified compound. Rf=0.50 (methanol/ethylacetate of 1/3).

EXAMPLE 57

[0522](±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0523] A. Synthesis of(±)-N-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 49)

[0524] The reaction and after-treatment were performed in accordancewith the procedures described in the steps A and B of Example 42 wherebythe above-identified compound (1.24 g) was obtained from Intermediate 13(1.72 g). Rf=0.65 (ethyl acetate/n-hexane of 1/2).

[0525] B. Synthesis of (±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 50)

[0526] The reaction and after-treatment were performed in accordancewith the procedures described in the step C of Example 42, whereby theabove-identified compound (544 mg) was obtained from Intermediate-49(873 mg) and Intermediate 5 (500 mg). Rf=0.49 (methanol/ethyl acetate of1/10).

[0527] C. Synthesis of (±)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0528] To a solution of 544 mg of Intermediate 50 in 30 ml oftetrahydrofuran, 1.75 ml of 4 N solution of hydrogen chloride/dioxanewere added and the mixture was agitated at room temperature for 1 hour,whereupon 30 ml of diethyl ether were added thereto and the crystalswere collected by filtration and dried under a reduced pressure toobtain 296.8 mg of the above-identified compound. Rf=0.67(methanol/ethyl acetate of 1/3).

EXAMPLE 58

[0529](±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0530] A. Synthesis of (±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 51)

[0531] The reaction and after-treatment were performed in accordancewith the procedures described in the step C of Example 42, whereby theabove-identified compound (122 mg) was obtained from Intermediate 49(480 mg) and Intermediate 39 (249.8 mg). Rf=0.45 (ethyl acetate/hexaneof 2/1).

[0532] B. Synthesis of (±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0533] To a solution of 122 mg of Intermediate 51 in 6 ml oftetrahydrofuran, 0.38 ml of 4 N solution of hydrogen chloride/dioxanewas added and the mixture was agitated at room temperature for 1 hour,whereupon diethyl ether was added thereto and the crystals werecollected by filtration and dried under a reduced pressure to obtain86.7 mg of the above-identified compound. Rf=0.76 (methanol/ethylacetate of 1/3).

EXAMPLE 59

[0534](±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamideHydrochloride

[0535] A. Synthesis of 1-[4-fluoro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone (Intermediate 52)

[0536] To a solution of 1 g of Intermediate 7 in 7.2 ml of pyridine, 708μl of dimethylaminosulfonyl chloride-were added at room temperature.After agitation for 3 days, the mixture was poured into 50 ml of waterand extraction with chloroform was carried out. The organic layer waswashed with saturated aqueous sodium chloride solution and dried,followed by evaporating under a reduced pressure to obtain a crudeproduct. Then, the above reaction and after-treatment were carried outonce more under the same condition and the resulting crude product waspurified by a column chromatography (2/1: n-hexane/ethyl acetate),whereby 1.1 g of above-identified compound were obtained. Rf=0.21 (ethylacetate/n-hexane of 1/2).

[0537] B. Synthesis of 2-bromo-1-[4-fluoro-3-[(dimethylsulfamoyl)amino]phenyl ethanone (Intermediate 53)

[0538] To a solution of 1.1 g of Intermediate 52 in 10 ml of1,4-dioxane, 229 μl of bromine were added under agitation. This mixturewas warmed to 60° C. and was agitated for 2.5 hours. After cooling downto room temperature, water was added thereto and extraction with ethylacetate was carried out, whereupon the organic layer was washedsaturated aqueous sodium chloride solution and dried, followed byconcentration under a reduced pressure to obtain the above-identifiedcompound as a crude product (1.588 g). Rf=0.52 (ethyl acetate/n-hexaneof 1/1).

[0539] C. Synthesis of (±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]-N,N-dimethylsulfamideHydrochloride

[0540] A modification of the procedures described in the step D ofExample 1 was employed, in which a solution of 1.58 g of Intermediate 53in 15 ml of anhydrous acetonitrile were added to a solution of 632 mg ofIntermediate 2 in a mixed solvent composed of 30 ml of anhydrousacetonitrile and 15 ml of anhydrous dimethylformamide under argonatmosphere at 0° C., whereupon 824 μl of triethylamine were addedthereto and the mixture was warmed to the room temperature (ca. 22° C.)and was agitated for 50 minutes.

[0541] To this mixture was then added a solution of 903 mg of sodiumborohyride in 30 ml of absolute ethanol at room temperature. Afteragitation for 70 minutes, the reaction was terminated using 1 Nhydrochloric acid (pH 4) and thereto was added 1.35 ml of ethanotamine.After agitation for 10 minutes, the mixture was diluted with 200 ml ofethyl acetate, organic layer was rinsed with saturated aqueous sodiumchloride solution three times and, then, dried, whereupon it wasevaporated under a reduced pressure to obtain a crude product. This waspurified by a column chromatography (methanol/chloroform of 1/20),whereby 276 mg of free amine product of the above-identified compoundwere obtained. Rf=0.66 (10% conc. aq. ammonia-containingmethanol/ethylacetate of 1/4).

[0542] To this, 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanolwere added to convert it into hydrochloride salt (the above-identifiedcompound), from which the solvent was distilled off under a reducedpressure. To the resulting residue was added ethanol/ethyl acetate, thethereby deposited precipitate was isolated by filtration and was driedunder a reduced pressure at 50° C., whereby 188.2 mg of theabove-identified compound were obtained as a powdery product.

EXAMPLE 60

[0543](±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamideHydrochloride

[0544] A. Synthesis of1-[4-chloro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone (Intermediate54)

[0545] To a solution of 1 g of Intermediate 11 in 6.5 ml of pyridine,640 μl of dimethylsulfamoyl chloride were added at room temperature andthe mixture was agitated for 28 hours. After heating the mixture at 40°C. for 65 hours, this was poured into water and extraction withchloroform was carried out. The organic layer was washed with saturatedaqueous sodium chloride solution and dried, followed by evaporatingunder a reduced pressure to obtain a crude product. This was purified bya column chromatography (n-hexane/ethyl acetate of 4/1), whereby 865 mgof the above-identified compound were obtained. Rf=0.24 (ethylacetate/n-hexane of 1/2).

[0546] B. Synthesis of 2-bromo-1-[4-chloro-3-[(dimethylsulfamoyl)amino]phenyl]ethanone (Intermediate 55)

[0547] To a solution of 860 mg of Intermediate 54 in 9 ml of1,4-dioxane, 168 μl of bromine were added under agitation. This mixturewas warmed to 60° C. and was agitated for 1.5 hours. After cooling downto room temperature, water was added thereto and extraction with ethylacetate was carried out whereupon the organic layer was washed saturatedaqueous sodium chroride solution and dried, followed by evaporatingunder a reduced pressure to obtain the above-identified compound as acrude product (1.05 g). Rf=0.55(ethyl acetate/n-hexane of 1/1).

[0548] C. Synthesis of (±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]-N,N-dimethylsulfamideHydrochloride

[0549] According to the procedures described in the step C of Example59, the Intermediate 2 (447 mg) was reacted with the Intermediate 55(1.05 g), followed by after-treatment and purification by a columnchromatography (methanol/chloroform of 1/20) and further by a PTLC (10%conc. aq. ammonia-containing methanol/ethyl acetate of 1/4), whereby251.1 mg of free amine product of the above-identified compound wereobtained. Rf=0.67 (10% conc. aq. ammonia-containing methanol/ethylacetate of 1/4).

[0550] To this, 1.1 equivalent amount of 0.1 N hydrogen chloride/ethanolwere added to convert it into hydrochloride salt (the above-identifiedcompound), from which the solvent was distilled off under a reducedpressure. To the resulting residue was added ethanol/ethyl acetate andthe thereby deposited precipitate was isolated by filtration and wasdried under a reduced pressure at 50° C., whereby 253.9 mg of theabove-identified compound were obtained as a powdery product.

EXAMPLE 61

[0551](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino)-1-hydroxyethyl]-3-benzyloxyphenyl]methanesulfonamide

[0552] A. Synthesis of 1-(3,5-dinitrophenyl)ethanone (Intermediate 56)

[0553] To a solution of 8 ml of dimethyl malonate in 70 ml of anhydroustetrahydrofuran, 78 ml of 0.92 M methyl magnesuimbromide/tetrahydrofuran (supplied from the firm Aldrich) were addeddropwise over a period of 30 minutes at a temperature of −10° C. orlower under argon atmosphere, Agitation was continued for further 15minutes and, then, a solution of 8.0 g of 3,5-dinitrobenzoyl chloride(supplied from Tokyo Chemical Industry Co., Ltd.) in 35 ml of chloroformwas added dropwise thereto over a period of 15 minutes. The temperatureof the reaction mixture was permitted to elevate to room temperature andagitation was continued for further 59 hours. The solvent was evaporatedoff from the reaction mixture under a reduced pressure and the resultingamorphous yellow residue (36.72 g) was dissolved in a mixture of 42 mlof acetic acid/35 ml of water, whereto 5 ml of concentrated sulfuricacid were added and the mixture was agitated with heating under refluxfor 5 hours. This reaction mixture was poured into 300 ml of ice waterand the deposited precipitate was separated by filtration. This waswashed with water and dried (6.35 g) at room temperature under a reducedpressure and was recrystallized from ethanol (5 ml), whereby 2.1 g ofthe above-identified compound were obtained; Rf=0.79 (ethylacetate/n-hexane of 1/2).

[0554] B. Synthesis of 1-(3-amino-5-nitrophenyl)ethanone (Intermediate57)

[0555] To a solution of 503 mg of Intermediate 56 in 10 ml of aceticacid, a solution of 1.43 g of stannous chloride (anhydrous) in 5 ml ofconcentrated hydrochloric acid were added dropwise over a period of 5minutes with agitation under cooling with salt/ice coolant. The mixturewas removed from the cooing bath and was agitated for three hours whilethe temperature was permitted to elevate gradually to room temperature.This reaction mixture was poured into 100 ml of saturated aqueous sodiumbicarbonate solution and the pH was adjusted at 8 by adding a furtheramount of saturated aqueous sodium bicarbonate solution, whereuponextraction with ethyl acetate (three times with each 50 μml) wasperformed. The organic layer was washed with saturated aqueous sodiumchloride solution and dried, followed by evaporating off of the solventunder a reduced pressure to obtain 160 mg of the above-identifiedcompound. Rf=0.51 (ethyl acetate/n-hexane of 1/2).

[0556] C. Synthesis of 1-(3-hydroxy-5-nitrophenyl)ethanone (Intermediate58)

[0557] 350 mg of Intermediate 57 were dissolved in 10 ml of sulfuricacid solution (prepared by adding 5 ml of water to 5 ml of concentratedsulfuric acid) and the mixture was agitated under ice-cooling, whereto 5ml of an aqueous solution of sodium nitrite (140 mg) were added dropwiseover a period of 5 minutes. After agitation for further 25 minutes, 10ml of the above sulfuric acid were added thereto and the mixture wasagitated with heating at 120° C. under reflux for 30 minutes. Aftercooling down to room temperature, extraction with ethyl acetate (twicewith each 40 ml) was performed. The organic layer was dried and thesolvent was distilled off under a reduced pressure, whereby 293 mg of acrude product were obtained. This was purified by a silica gelchromatography (elution with chloroform−methanol/chloroform of3/97-5/95), whereby 154 mg of the above-identified compound wereobtained. Rf=0.40 (methanol/chloroform of 1/9).

[0558] D. Synthesis of 1-(3-benzyloxy-5-nitrophenyl)ethanone(Intermediate 59)

[0559] 154 mg of Intermediate 58 were dissolved in 5 ml of anhydrousdimethylformamide and thereto were added 360 mg of anhydrous potassiumcarbonate, 0.22 ml of benzyl bromide and 130 mg of sodium iodide,successively, and the mixture was agitated for 11.5 hours. Then, 10 mlof water were added to the reaction mixture to terminate the reactionand thereto were added further 50 ml of water, whereupon extraction withethyl acetate (twice with each 50 ml) was performed. Organic layer waswashed with 100 ml of water and with saturated aqueous sodium chloridesolution, successively, followed by drying and distilling off of thesolvent under a reduced pressure, whereby 277 mg of a crude product wereobtained. This was purified by a silica gel chromatography (elution withethyl acetate/n-hexane of 1/9), whereby 140 mg of the above-identifiedcompound were obtained. Rf=0.91 (methanol/chloroform of 1/9).

[0560] E. Synthesis of 1-(3-amino-5-benzyloxyphenyl)ethanone(Intermediate 60)

[0561] 140 mg of Intermediate 59 were dissolved in 20 ml of methanol andthereto were added 5 mg of platinum oxide under argon atmosphere,whereupon the reaction system was replaced with hydrogen gas underice-cooling. The mixture was agitated for 11.5 hours under ice-cooling,whereupon the reaction system was replaced with argon and 20 ml ofchloroform were added thereto. After the catalyst has been removed byfiltration, the solvent was distilled off from the filtrate under areduced pressure, whereby 116 mg of the above-identified compound wereobtained. Rf=0.82 (methanol/chloroform of 1/9).

[0562] F. Synthesis of1-[3-benzyloxy-5-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate61)

[0563] According to the method reported by A. A. Larsen in J. Med.Chem., 10, 462 472 (1967), reaction and after-treatment were performed,whereby 142 mg of the above-identified compound were obtained from 116mg of Intermediate 60 and 40 μl of methanesulfonyl chloride throughpurification by silica gel chromatography (elution withmethanol/chloroform of 5/95). Rf=0.47 (methanol/chloroform of 1/9).

[0564] G. Synthesis of 2-bromo-1-[3-benzyloxy-5-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate 62)

[0565] In the same manner as the procedures described in the step A ofExample 29, 172 mg of the above-identified compound were obtained from140 mg of Intermediate 61 and 223 mg of cupric bromide. Rf=0.78 (ethylacetate/n-hexane of 1/1).

[0566] H. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-benzyloxyphenyl]methanesulfonamide

[0567] In accordance with the procedures described in the step D ofExample 1, 55 mg, of the above-identified compound were obtained from170 mg of Intermediate 62 and 95 mg of Intermediate 2. Rf=0.28(methanol/chloroform of 1/9).

EXAMPLE 62

[0568](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-3-hydroxyphenyl]methanesulfonamideHydrochloride

[0569] In accordance with the procedure described in Example 2, 55 mg ofthe compound of Example 61 were subjected to a hydrogenolysis using 10%palladium/carbon black (27.5 mg), whereby 30.6 mg of theabove-identified compound were obtained. Here, however, the crudeproduct was purified in a usual manner by converting it intohydrochloride salt which was recrystallized from methanol/ethyl acetate.Rf=0.05(methanol/chloroform of 1/9).

EXAMPLE 63

[0570](±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0571] A. Synthesis of 1-(2-hydroxy-3-nitrophenyl)ethanone (Intermediate63) and 1-(2-hydroxy-5-nitrophenyl)-ethanone (Intermediate 64)

[0572] 13.2 g of 2-hydroxyacetophenone (supplied from the firm Aldrich)were dissolved in 140 ml of concentrated sulfuric acid underice-cooling, whereto 9.66 g of potassium nitrate were added. The mixturewas agitated at 10-15° C. for 105 minutes, whereto a total of 2.8 g ofpotassium nitrate were further added in three portions over a period of8 hours until the starting material has been consumed. Then the mixturewas agitated for 14 hours under ice-cooling and the resulting reactionmixture was poured into two liters of ice-water mixture, followed byextraction with ethyl acetate (twice with each 500 ml), whereupon theorganic layer was washed with saturated aqueous sodium chloride solutionand dried, before the solvent was distilled off under a reduced pressureto obtain 19.23 g of a crude product. This was purified by a silica gelchromatography, whereby 6.0 g of Intermediate 64 were obtained fromelution fractions with ethyl acetate/n-hexane of 1/9 and 9.5 g ofIntermediate 63 were obtained from elution fractions with ethylacetate/n-hexane of 1/4.

[0573] Intermediate 63: Rf=0.19 (ethyl acetate/n-hexane of 1/4)

[0574] Intermediate 64: Rf=0.49 (ethyl acetate/n-hexane of 1/4)

[0575] B. Synthesis of 1-(2-methoxy-3-nitrophenyl)ethanone (Intermediate65)

[0576] 2.29 g of Intermediate 63 were dissolved in 20 ml of anhydrousdimethylformamide and thereto were added 5.2 g of anhydrous potassiumcarbonate, and 1.56 ml of methyl iodide, successively, whereupon themixture was agitated for 18 hours. Then, 50 ml of water were added tothe reaction mixture to terminate the reaction, whereupon extractionwith ethyl acetate (6 times with each 50 ml) was performed. The organiclayer was washed with saturated aqueous sodium chloride solution,followed by drying and distilling off of the solvent under a reducedpressure, whereby 2.29 g of a crude product were obtained. This wasfurther dried under a reduced pressure with vacuum pump, whereby 1.87 gof the above-identified compound were obtained. Rf=0.58 (ethylacetate/n-hexane of 1/2).

[0577] C. Synthesis of 1-(3-amino-2-methoxyphenyl)ethanone (Intermediate66)

[0578] 1.87 g of Intermediate 65 were dissolved in 150 ml of methanoland thereto were added 90 mg of platinum oxide under argon atmosphere,whereupon the reaction system was replaced with hydrogen gas underice-cooling. The mixture was agitated at room temperature for 5 hoursand the reaction system was replaced with argon gas, followed byaddition of 50 ml of chloroform. The catalyst was filtered off and thesolvent was distilled off from the filtrate under a reduced pressure,whereby 1.59 g of the above-identified compound were obtained. Rf=0.74(methanol/chloroform of 1/9).

[0579] D. Synthesis of 1-[2-methoxy-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate 67)

[0580] According to the method reported by A. A. Larsenin J. Med. Chem.,10, 462-472 (1967), the above compound was produced from Intermediate 66(1.59 g) and methanesulfonyl chloride (750 μl). Here, however, thefollowing alteration was incorporated in the purification step from thereaction mixture. Thus, the reaction was terminated with water (50 ml)and the mixture was agitated for 12 hours before extraction with ethylacetate (once with 50 ml and twice with each 30 ml) with subsequentwashing with 1 N hydrochloric acid (twice with each 25 ml) and withsaturated aqueous sodium chloride solution, successively, followed bydistilling off of the solvent under a reduced pressure, whereby theabove-identified compound was obtained (1.93 g). Rf=0.55(methanol/chloroform of 1/19).

[0581] E. Synthesis of 1-[2-methoxy-3-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone (Intermediate 68)

[0582] 1.93 g of Intermediate 67 were dissolved in 15 ml of anhydrousdimethylformamide and thereto were added at room temperature 3.32 g ofanhydrous potassium carbonate, 1.9 ml of benzyl bromide and 1.2 g ofsodium iodide, successively, and the mixture was agitated for 14 hours.Then, 50 ml of water were added to the reaction mixture to terminate thereaction, whereupon extraction with ethyl acetate (thrice with each 40ml) was performed. Organic layer was washed with water (twice with each50 ml) and with saturated aqueous sodium chloride solution,successively, followed by drying and distilling off of the solvent undera reduced pressure, whereby 3.04 g of a crude product were obtained.This was purified by a silica gel chromatography (elution with ethylacetate/n-hexane of 1/4-1/2), whereupon fractions containing the targetcompound were processed by evaporating and recrystallization from ethylacetate/n-hexane to obtain the above-identified compound (2.00 g).Rf=0.75 (methanol/chloroform of 1/19).

[0583] F. Synthesis of2-bromo-1-[2-methoxy-3-[N-benzyl-N-(methylsulfonyl)amino]phenyl)ethanone(Intermediate 69)

[0584] In the same manner as the procedures described in the step A ofExample 29, 438 mg of the above-identified compound were obtained from333 mg of Intermediate 68 and 491 mg of cupric bromide. Rf=0.36 (ethylacetate/n-hexane of 1/2).

[0585] G. Synthesis of(±)-N-benzyl-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-methoxyphenyl]methanesulfonamide(Intermediate 70)

[0586] According to the procedures described in the step D of Example 1,the above-identified compound (150 mg) was obtained from Intermediate 69(438 mg) and Intermediate 2 (215 mg). Rf=0.74 (methanol/chloroform of1/9).

[0587] H. Synthesis of(±)-N-benzyl-N-(3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride (Intermediate 71)

[0588] To a solution of 100 mg of Intermediate 70 in 10 ml of anhydrousdichloromethane, 0.60 ml of 1 M solution of boron tribromide indichloromethane (supplied from the firm Aldrich) was added dropwiseunder cooling with dry ice/acetone coolant. The mixture was agitated assuch for 30 minutes and, then, agitation was continued for further 30minutes under ice-cooling. The reaction was terminated by addingsaturated aqueous sodium bicarbonate solution to the reaction mixtureand extraction with ethyl acetate was carried out (four times with each30 ml). The organic layer was washed with saturated aqueous sodiumchloride solution with subsequent drying, whereupon the solvent wasdistilled off under a reduced pressure. The resulting residue waspurified by a silica gel chromatography (elution with chloroform/ethylacetate/10% of conc. aq. ammonia-containing methanol of 16/3/1-6/3/1),whereby 69 mg of free amine product of the above-identified compoundwere obtained. Rf=0.47 (methanol/chloroform of 1/9).

[0589] This was converted into hydrochloride salt using 0.1 NHCl/ethanol, whereby 28 mg of the above-identified compound wereobtained by recrystallization from methanol/ethyl acetate. Here. 38 mgof the above-identified compound were recovered also from the filtrate.

[0590] I. Synthesis of (±)-N-[3-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0591] According to the precedures described in Example 2, theabove-identified compound (17.3 mg) was obtained from Intermediate 71and the recovered product from the filtration (total sum of 55 mg) bysubjecting them to a hydrogenolysis using 10% palladium/carbon black (55mg) for 13 hours with subsequent recrystallization of the resultingcrude product (25 mg) from methanol/ethyl acetate. Rf=0.41(methanol/chloroform of 1/9).

EXAMPLE 64

[0592](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamideHydrochloride

[0593] A. Synthesis of 1-(2-methoxy-5-nitrophenyl)ethanone (intermediate72)

[0594] The above-identified compound (2.50 g) was obtained by processingIntermediate 64 (2.36 g) resulting from the step A of Example 63 throughreaction and after-treatment in accordance with the procedures of thestep B of Example 63. Rf=0.37(ethyl acetate/n-hexane of 1/2).

[0595] B. Synthesis of 1-(5-amino-2-methoxyphenyl)ethanone (Intermediate73)

[0596] The above-identified compound (2.13 g) was obtained by processingIntermediate 72 (2.50 g) through reaction and after-treatment inaccordance with the procedures of the step C of Example 63. Rf=0.38(methanol/chloroform of 1/19).

[0597] C. Synthesis of 1-[2-methoxy-5-[(methylsulfonylamino]phenyl]ethanone(Intermediate 74)

[0598] The above-identified compound (2.656 g) was obtained byprocessing Intermediate 73 (2.13 g) through reaction and after-treatmentin accordance with the procedures of the step D of Example 63. Rf=0.35(methanol/chloroform of 1/19).

[0599] D. Synthesis of 1-[2-methoxy-5-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone (intermediate 75)

[0600] A crude product (4.29 g) was obtained by processing Intermediate74 (2.65 g) through reaction and after-treatment in accordance with theprocedures of the step E of Example 63. By purifying this crude productby a silica gel column chromatography (elution with ethylacetate/n-hexane of 1/4-1/2-2/3) and processing the fractions containingthe target compound by evaporating and recryatallization from ethylacetate/n-hexane, the above-identified compound (2.553 g) was obtained.Rf=0.68 (methanol/chloroform of 1/19).

[0601] E. Synthesis of2-bromo-1-[2-methoxy-5-[N-benzyl-N-(methylsulfonyl)amino]phenyl]ethanone(Intermediate 76)

[0602] In the same manner as the procedures described in the step A ofExample 29, the above-identified compound (436 mg) was obtained fromIntermediate 75 (333 mg) and cupric bromide (491 mg). Rf=0.28 (ethylacetate/n-hexane of 1/2).

[0603] F. Synthesis of(±)-N-benzyl-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-methoxyphenyl]methanesulfonamide(Intermediate 77)

[0604] In accordance with the procedures described in the step D ofExample 1, the above-identified compound (70 mg) was obtained fromIntermediate 76 (436 mg) and Intermediate 2 (215 mg). Rf=0.52(methanol/chloroform of 1/9).

[0605] G. Synthesis of(±)-N-benzyl-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamidehydrochloride (Intermediate 78)

[0606] The free base product (39 mg) was obtained by processingIntermediate 77 (70 mg) through reaction and after-treatment inaccordance with the procedures of the step H of Example 63 andpurification by a silicagel chromatography (elution withchloroform/ethyl acetate/10% of conc. aq. ammonia-containing methanol of16/3/1-6/3/1). Rf=0.50 (methanol/chloroform of 1/9). By converting thisproduct into hydrochloride salt using 0.1 N hydrogen chloride/ethanolwith subsequent recrystallization from methanol/ethyl acetate, theabove-identified compound (17 mg) was obtained.

[0607] H. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-4-hydroxyphenyl]methanesulfonamideHydrochloride

[0608] According to the procedures described in Example 2, Intermediate78 and the recovered product from the filtration (total sum of 30 mg)were treated by subjecting them to a hydrogenolysis for 13 hours using10% palladium/carbon black (30 mg) with subsequent trituration of theresulting crude product from methanol/ethyl acetate, whereby theabove-identified compound, (9 mg) was obtained. Rf=0.34(methanol/chloroform of 1/9).

EXAMPLE 65

[0609](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamideHydrochloride

[0610] A. Synthesis of N-methyl-(2-benzyloxy-4-acetylbenzene)sulfonamide (intermediate 80)

[0611] 2.41 g of 1-(3-amino-4-benzyloxyphenyl)ethanone[prepared by themethod reported by A. A. Larsen et al in J. Med. Chem., 10, 462-472(1967)] were dissolved in 5 ml of acetic acid and thereto were adde 5 mlof concentrated hydrochloric acid. To this mixture, 7 ml of an aqueoussolution of sodium nitrite (1.0 g) were added over a period of 50minutes at −10° C. with agitation. Agitation was continued further for28 minutes under ice-cooling and thereto were added a solution of 3.5 mlof thionyl chloride in 6.5 ml of acetic acid and 3 ml of an aqueoussolution of cupric chloride dihydrate (720 mg), successively, whereuponthe mixture was agitated for 6 hours, while the temperature was allowedto return to room temperature. The deposited precipitate was separatedby filteration and was dissolved in chloroform, followed by waterwashing and drying with subsequent evaporating up to a volume of 50 mlunder a reduced pressure, whereby a solution of2-benzyloxy-5-acetylbenzenesulfonylchloride (Intermediate 79) inchloroform was prepared.

[0612] Thereto was added 1.0 ml of 40% aqueous solution of methylamineand the mixture was agitated at room temperature for 16.5 hours. To thisreaction mixture, 50 ml of water were added and the organic layer wasseparated. The aqueous layer was extracted once with chloroform (50 ml)and the extract was brought together with the above organic layer andwas rinsed with saturated aqueous sodium chloride solution, followed bydrying, whereupon the solvent was distilled off under a reducedpressure. Resulting residue was purified by a silica gelchromatography(chloroform−methanol/chloroform of 1/19), whereby 200 mgof the above-identified compound were obtained. Rf=0.05 (chloroform).

[0613] B. Synthesis of N-methyl-[2-benzyloxy-4-(2-bromoacetyl)benzenesulfonamide (Intermediate 81)

[0614] In the same manner as the procedures described in the step A ofExample 29, the above-identified compound (248 mg) was obtained fromIntermediate 80 (200 mg) and cupric bromide (310 mg). Rf=0.83 (ethylacetate/n-hexane of 1/1).

[0615] C. Synthesis of (±)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide

[0616] In the same manner as in the procedures described in the step Dof Example 1 except that a silicagel chromatography (methanol/ethylacetate of 1/19-1/9) was employed for the purification of the crudeproduct, the above-identified compound (118 mg) was obtained fromIntermediate 81 (248 mg) and Intermediate 2 (136 mg). Rf=0.55(methanol/chloroform of 1/9).

EXAMPLE 66

[0617](±)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamideHydrochloride

[0618] In accordance with the procedure described in Example 2, thecompound of Example 65 (110 mg) were subjected to a hydrogenolysis using10% palladium/carbon black (55 mg) for 1 hour, whereby theabove-identified compound (39 mg) was obtained. Rf=0.05(methanol/chloroform of 1/9).

EXAMPLE 67

[0619](±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanolHydrochloride

[0620] A. Synthesis of 2-benzyloxy-5-acetylbenzoic acid methyl ester(Intermediate 82)

[0621] 1.94 g of 5-acetylsalicylic acid methyl ester (supplied from thefirm AVOCADO) were dissolved in 15 ml of anhydrous dimethylformamide andthereto were added 4.2 g of anhydrous potassium carbonate. 2.5 ml ofbenzyl bromide and 3.3 g of sodium iodide, successively, whereupon themixture was agitated for 60 hours. The reaction was terminated by adding15 ml of water to the reaction mixture and th mixture was agitated withice-cooling. The deposited precipitate was separated by filtration,washed with water and dried under a reduced pressure at 50° C. (2.83 g).This was recrystallized from toluene/n-hexane and 2.54 g of theabove-identified compound were obtained. Rf=0.32 (ethyl acetate/n-hexaneof 1/2).

[0622] B. Synthesis of 2-benzyloxy-5-(2-bromoacetyl)benzoic Acid MethylEster (Intermediate 83)

[0623] In the same manner as the procedures described in the step A ofExample 29, the above-identified compound (566 mg) was obtained fromIntermediate 82(1.42 g) and cupric bromide (151 mg). Rf=0.71(methanol/chloroform of 1/19).

[0624] C. Synthesis of (±)-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzoic Acid Methyl Ester(Intermediate 84)

[0625] According to the procedures described in the step D of Example 1,the above-identified compound (80 mg) was obtained from Intermediate 2(154 mg), triethylamine (150 μl). Intermediate 83 (191 mg) and sodiumborohydride (151 mg). Rf=0.24 (methanol/chloroform of 1/9).

[0626] D. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yloxy)ethyl]amino]-1-[4-benzyloxy-3-(hydroxymethyl)phenyl]ethanol(Intermediate 85)

[0627] To a suspension of 2 mg of lithium aluminum hydride in 5 ml ofanhydrous tetrahydrofuran, a solution of 34 mg of Intermediate 84 in 5ml of anhydrous tetrahydrofuran was added. After agitation for 30minutes, reaction was terminated by adding 1 ml of ethyl acetate and 1ml of 1 N HCl and the aqueous layer was adjusted at pH 10, whereuponextraction with ethyl acetate (twice with each 20 ml) was performed. Theorganic layer was dried and the solvent was distilled off under areduced pressure, whereupon the resulting residue (28 mg) was purifiedby a silica gel chromatography (methanol/chloroform of 1/9-1/7) toobtain 24 mg of the above-identified compound. Rf=0.05(methanol/chloroform of 1/9).

[0628] E. Synthesis of(±)-2-[N-[2-(9H-carbazol-2-yl-oxy)ethyl]amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanolHydrochloride

[0629] In accordance with the procedure described in Example 2,Intermediate 85 (24 mg) was added to methanol (5 ml) and was subjectedto a hydrogenolysis using 10% palladium/carbon black (12 mg) for 2.5hours, whereby the above-identified compound (8.9 mg) was obtained.Rf=0.21 (methanol/chloroform of 1/7).

EXAMPLE 68

[0630](t)-N-[3-[2-[2-(9H-6-(acetylamino)carbazol-2-yloxy]ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0631] A. Synthesis of(±)-N-[3-(2-bromo-1-hydroxyethyl)phenyl]methanesulfonamide (Intermediate86)

[0632] The above-identified compound (50.76 g) was obtained byprocessing Intermediate 14 (45 g) through reaction and after-treatmentin accordance with the procedures of synthesis of Intermediate 41.Rf=0.27 (methanol/chloroform of 1/10).

[0633] B. Synthesis of(±)-N-[3-[2-iodo-1-(triethylsilyloxy)ethyl]phenyl]methanesulfonamide(Intermediate 87)

[0634] According to the method for synthesizing Intermediate 42,Intermediate 86 (50.1 g) was dissolved in dried acetone (944 ml) andthereto was added sodium iodide (257.57 g) and the mixture was agitatedwith heating under reflux for 2.5 hours. Then, the mixture was cooleddown to room temperature and was filtered, whereupon the filtrate wasevaporated to dryness under a reduced pressure. The resulting residuewas subjected to extraction with 720 ml of dichloromethane and 720 ml ofwater, followed by washing of the organic layer with 23.5% (w/w) ofaqueous sodium hydrogen sulfite solution (twice), with water and withsaturated aqueous sodium-chloride solution, successively, and drying,whereupon the solvent was distilled off under a reduced pressure. Theresidue was further dried under a reduced pressure using a vacuum pump,whereby 51.61 g of a viscous fluid product was obtained. This wasdissolved in 351 ml of anhydrous dimethylformamide at room temperature,whereto 28.3 g of imidazole and 1.61 g of 4-dimethylaminopyridine andthe resulting mixture was agitated for 15 minutes. Thereto were added27.04 ml of chlorotrimethylsilane all at once and the mixture wasagitated at room temperature for 40 minutes. The resulting mixture wasthen diluted with 840 ml of ethyl acetate and 336 ml of n-heptane andwas then washed with water (420 ml), with 2% aqueous solution of coppersulfate (twice with each 420 ml), with water (420 ml) and finally withsaturated aqueous sodium chloride solution (420 ml), successively, anddried, whereupon the solvent was distilled off under a reduced pressureto obtain 68.25 g of the above-identified compound. Rf=0.48(methanol/chloroform of 1/10).

[0635] C. Synthesis of 4-acetylaminocyclohexanone (Intermediate 88)

[0636] To a suspension of 20.85 g of trans-4-acetamidecyclohexanol in21.6 ml of water under ice-cooling, Jone's Reagent prepared from 9.28 gof cromium trioxide. 8.1 ml of concentrated sulfuric acid and 33.4 ml ofwater was added over a period of 8 minutes under ice-cooling. Theresulting mixture was agitated for further 5 hours under ice-cooling,whereupon it it was stored in a refrigerator for 2 days. This wassubjected to extraction with chloroform (10 times with each 70 ml),followed by washing with saturated aqueous sodium bicarbonate solutionand drying, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was further dried at room temperatureunder a reduced pressure, whereby 8.45 g of the above-identifiedcompound were obtained. Rf=0.40(methanol/chloroform of 1/10).

[0637] D. Synthesis of(±)-3-acetylamino-7-methoxy-1,2.3,4-tetrahydrocarbazole (Intermediate89)

[0638] 9.77 g of 3-methoxyphenylhydrazine hydrochloride (supplied fromthe firm ACROS) and 8.58 g of Intermediate 88 were dissolved in 83 ml ofethanol, whereto 35 ml of 4 N hydrogen chloride/1,4-dioxane (suppliedfrom the firm Aldrich) were added and the mixture was heated underreflux for 3 hours. The resulting mixture was cooled down to roomtemperature and precipitate was filtered off and the solvent in thefiltrate was distilled off under a reduced pressure. To the resultingresidue, ethanol/n-heptane was added and the resulting mixture wasevaporated to dryness, whereupon the residue was dissolved in a smallamount of ethanol, whereto water was added and the deposited precipitatewas triturated and isolated by filtration, followed by water washing anddrying at 42° C. under a reduced pressure. This was then treated bytrituration with small amount of ethanol, crystallization from ethylacetate (200 ml), filtration of crystals, washing with ethyl acetate anddrying under a reduced pressure at room temperature to obtain 5.188 g ofthe above-identified compound as primary crystals. Rf=0.45(methanol/chloroform of 1/10).

[0639] E. Synthesis of 9H-6-acetylamino-2-methoxycarbazole (Intermediate90)

[0640] 5.188 g of Intermediate 89 and 9.459 g of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (97%) were heated under refluxin benzene for 7.5 hours under argon atmosphere. The reaction mixturewas filtered with heating and the filtered cake was washed with hotbenzene. The filtrate and the washed liquor were brought together, fromwhich the solvent was distilled off under a reduced pressure. To theresult ting residue, ethanol was added and the deposited product wasisolated by filtration, whereby 269 mg of the above-identified compound(primary crystals) were obtained. Rf=0.39 (methanol/chloroform of 1/10).

[0641] F. Synthesis of 9H-6-acetylamino-2-hydroxycarbazole (Intermediate91)

[0642] 269 mg of Intermediate 90 were added at 180° C. to pyridinehydrochloride (prepared by heating 5 ml of pyridine and 5 ml ofconcentrated hydrochloric acid at 180° C. for 1.5 hours to dehydrate)and the mixture was agitated with heating under reflux for 4 hours. Theresulting mixture was poured into 100 ml of ice and was then subjectedto extraction with ethyl acetate. The aqueous layer was adjusted at pH 7and was treated by a further extraction with ethyl acetate. Both organiclayers were brought together and are washed with saturated aqueoussodium chloride solution, followed by drying, whereupon the solvent wasdistilled off under a reduced pressure. The resulting residue (182.1 mg)was dissolve in pyridine (5 ml), whereto 1 ml of acetic anhydride wasadded and the mixture was agitated at room temperature for 12 hours. Theresulting mixture was diluted with 50 ml of water and was then subjectedto extraction with ethyl acetate, followed by washing with water andthen with saturated aqueous sodium chloride solution with subsequentdrying, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was dissolved in 4 ml of methanol (MS3Agrade), whereto 1 ml of water and 0.5 ml of 5 N aqueous sodium hydroxidesolution were added and the mixture was agitated at room temperature for45 minutes. Then, the mixture was diluted with 40 ml of water andadjusted at pH 3 with 1N hydrochloric acid, whereupon extraction withethyl acetate was effected three times for this mixture. The resultingorganic layers were-washed with saturated aqueous sodium chloridesolution with subsequent drying, followed by distilling off of thesolvent under a reduced pressure, whereby 163.8 mg of theabove-identified compound were obtained. Rf=0.10(methanol/chloroform of1/10).

[0643] G. Synthesis of9H-6-acetylamino-2-(2-benzyloxycarbonylaminoethoxy)carbazole(Intermediate 92)

[0644] According to the procedures described in the step B of Example 1,520 mg of Intermediate 0 were added to a solution of 161 mg ofIntermediate 91 and 470 mg of potassium carbonate in dimethylformamide(1.7 ml) and the mixture was agitated at room temperature for 11.5 hourswith further agitation at 50° C. for 8 hours. Thereto were added ethylacetate and water, followed by extraction with ethyl acetate twice andwashing with water and with saturated aqueous sodium chloride solution,successively, drying and distilling off of the solvent under a reducedpressure, whereupon the resulting residue was purified by a columnchromatography (methanol/chloroform of 3/100-6/100), whereby 105.8 mg ofthe above-identified compound were obtained. Rf=0.37(methanol/chloroform of 1/10).

[0645] H. Synthesis of 2-(9H-6-acetylaminocarbazol-2-yloxy) ethylamine(Intermediate 93)

[0646] To 105.8 mg of Intermediate 92, 2.1 ml of 30% solution ofhydrogen bromide in acetic acid were added and the mixture was agitatedat room temperature for 1.5 hours. Thereto were added 50 ml of diethylether and the deposited precipitate was isolated by filtration. This wasdissolved in water and the pH was adjusted at 10 with aqueous NaOH andwas subjected to extraction with ethyl acetate. After drying the organiclayer, the solvent thereof was distilled off under a reduced-pressure,whereby 80.1 mg of the above-identified compound were obtained. Rf=0.05(methanol/chloroform of 1/5).

[0647] I. Synthesis of (±)-N-[3-[2-[2-[9H-6-(acetylamino)carbazol-2-yloxy]ethyamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0648] 117.5 mg of Intermediate 87 and 80, 1 mg of Intermediate 93 weredissolved in 0.5 ml of anhydrous dimethylacetamide and thereto wereadded 493 μl of Hunig Base, whereupon the mixture was agitated at 60° C.for 27 hours under argon atmosphere. Then, the mixture was cooled downto room temperature and was diluted with ethyl acetate, followed bywashing water (twice) and then with saturated aqueous sodium chloridesolution and drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was dissolved in ethyl acetateand the insoluble matter was filtered off, whereupon the filtrate wasevaporated under a reduced pressure. The resulting residue was subjectedto a primary purification by a silica gel chromatography(methanol/chloroform of 5/100-1/10).

[0649] Fractions containing a product which is positive to ninhydrincoloration were united and the so-united fractions were evaporated todryness. The resulting product (49.6 mg) was dissolved in 2.7 ml ofanhydrous tetrahydrofuran and thereto were added 35 μl of acetic acidand 535 μl of 1 M tetrabutylammonium fluoride/tetrahydrofuran and theresulting mixture was agitated at room temperature for 1 hour in atightly closed vessel. The resulting mixture was diluted with ethylacetate, followed by washing with saturated aqueous sodium bicarbonatesolution and, then, with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. By purifying the resulting residue, by a silica gelchromatography (with-eluting off low polar impurities withmethanol/chloroform of 1/10 and eluting with conc. aq.ammonia/methanol/chloroform of 1/9/50), 30.5 mg of free amine product ofthe above-identified compound were obtained. This was converted intohydrochloride salt by a usual technique, followed by dissolution insmall amount of methanol, dilution with ethyl acetated, crystallizationand collecting by filteration, 29.5 mg of the above-identified compoundwere obtained. Rf=0.14 (methanol/chloroform of 1/5).

EXAMPLE 69

[0650](R)-N-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0651] In accordance with the procedures described in Example 12, theabove-identified compound (37.6 mg) was obtained from Intermediate 19(220 mg) and Intermediate 5 (121.7 mg).

[0652] Retention time: 36.3 min. for R-modification (41.7 min. forS-modification); Analytical condition: column: two sets, 4.6 mm×150 mm.CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase 0.5 MNaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 70

[0653](R)-N-[3-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0654] In accordance with the procedures described in Example 14, theabove-identified compound (167.0 mg) was obtained from Intermediate 26(815 mg) and Intermediate 5 (455 mg).

[0655] Retention time: 28.7 min. for R-modification (25.4 min. forS-modification); Analytical condition: column: two sets. 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase 0.5 MNaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 71

[0656](R)-N-[3-[2-[2-(9H-7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamideHydrochloride

[0657] In accordance with the procedures described in Example 14, theabove-identified compound (55.5 mg) was obtained from Intermediate 26(815 mg) and Intermediate 17 (564.6 mg).

[0658] Retention time: 77.6 min. for R-modification (64.7 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.): mobile phase: 0.5M NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (8/2); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 72

[0659](R)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0660] In accordance with the procedures described in Example 12, theabove-identified compound (223.2 mg) was obtained from Intermediate 19(642 mg) and Intermediate 39 (380 mg).

[0661] Retention time: 36.3 min. for R-modification (38.6 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M NaClO₄/HCl₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 73

[0662](R)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0663] A. Synthesis of(R)-N′-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxyphenyl]-N,N-dimethylsulfamide

[0664] In accordance with the procedures described in the synthesis ofIntermediate 19, the above-identified compound (925.7 mg) was obtainedfrom Intermediate 40 (1.058 g).

[0665] Retention time: 19.6 min. for R-modification (17.4 min. forS-modification): Analytical condition: column: 4.6 mm ID×250 mm,CHIRALCEL OJ (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1): flow rate: 0.7 ml/min.; detection: 254 nm:temperature: R.T.

[0666] B. Synthesis of (R)-N′-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide (Intermediate 94)

[0667] In the same manner as in the synthesis of Intermediate 42(racemic), the above-identified compound (1.27 g) was obtained fromabove-mentioned Intermediate (925 mg) in two process steps.

[0668] C. Synthesis of (R)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 95)

[0669] In the same manner as the synthesis of Intermediate 43, theabove-identified compound (262.2 mg) was obtained from Intermediate 94(590 mg) and Intermediate 2 (294 mg). Rf=0.54 (methanol/chloroform of1/10).

[0670] D. Synthesis of (R)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 96)

[0671] In accordance with the procedures described in Example 42, theabove-identified compound (83.7 mg) was obtained from Intermediate 95(120 mg).

[0672] E. Synthesis of (R)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0673] The above-identified compound (75.6 mg) was obtained by reactionand after-treatment of Intermediate 96 (82 mg) in accordance with theprocedures described in Example 25.

[0674] Retention time: 38.0 min. for R-modification (47.7 min. forS-modification); Analytical condition: column: two sets. 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase 0.5 MNaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate: 0.5ml/min.; detection: 254 nm: temperature: 40° C.

EXAMPLE 74

[0675](S)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0676] A. Synthesis of(S)-N′-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxyphenyl]-N,N-dimethylsulfamide

[0677] In accordance with the procedures of synthesis of Intermediate19, the above-identified compound (928.1 mg) was obtained fromIntermediate 40(1.05 g) using as the asymmetric catalyst an(S)-modification.

[0678] Retention time: (19.6 min. for R-modification) 17.4 min. forS-modification; Analytical condition: column: 4.6 mm ID×150 mm,CHIRALCEL OJ (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1); flow rate: 0.7 ml/min.; detection: 254 nm;temperature: R.T.

[0679] B. Synthesis of (S)-N′-[5-[2-iodo-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide (Intermediate 97)

[0680] In the same manner as in the synthesis of Intermediate 42(racemic), the above-identified compound (1.18 g) was obtained fromabove-mentioned Intermediate (868.1 mg) in two process steps.

[0681] C. Synthesis of (S)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-(triethylsilyloxy)ethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 98)

[0682] In the same manner as the synthesis of Intermediate 43, theabove-identified compound (120.8 mg) was obtained from Intermediate 97(300 mg) and Intermediate 2 (144 mg).

[0683] D. Synthesis of (S)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxyphenyl]-N,N-dimethylsulfamide(Intermediate 99) In accordance with the procedures-described for thesynthesis of the compound Example 42, the above-identified compound(83.7 mg) was obtained from Intermediate 98 (120.8 mg>.

[0684] E. Synthesis of (S)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N N-dimethylsulfamideHydrochloride

[0685] The above-identified compound (42.3 mg) was obtained by reactionand after-treatment of Intermediate 99 (65.8 mg) in accordance with theprocedures described in Example 25.

[0686] Retention time: (38.5 min. for R-modification) 47.7 min. forS-modification; Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.): mobile phase: 0.5AM NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3): flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 75

[0687](R)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0688] In accordance with the procedures described in Example 73, theabove-identified compound (32.9 mg) was obtained from Intermediate 94(240 mg) and Intermediate 5 (115.4 mg).

[0689] Retention time: 18.3 min. for R-modification (21.5 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm. CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase 0.5 MNaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (6/4); flow rate: 0.5ml/min.; detection: 254 nm; temperature 40° C.

EXAMPLE 76

[0690](S)-N′-[5-[2-[2-(dibenzofuran-3-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamideHydrochloride

[0691] In accordance with the procedures described in Example 74, theabove-identified compound (39.6 mg) was obtained from Intermediate 97(240 mg) and Intermediate 5 (114.4 mg).

[0692] Retention time: (18.3 min. for R-modification) 21.5 min. forS-modification; Analytical condition: column: two sets. 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M[NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (6/4): flow rate:0.-5 ml/min.; detection: 254 nm, temperature: 40° C.

EXAMPLE 77

[0693](R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0694] A. Synthesis of(R)-N-[5-(2-bromo-1-hydroxyethyl)-2-fluorophenyl]methanesulfonamide(Intermediate 100)

[0695] In accordance with the procedures described in the synthesis ofIntermediate 19 the above-identified compound (1.79 g) was obtained fromIntermediate 9 (1.53 g) by reaction and after-treatment.

[0696] Retention time: 31.1 min. for R-modification (33.3 min. forS-modification); Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1); flow rate: 0.3 ml/min.; detection: 254 nm:temperature: R.T.

[0697] B. Synthesis of (R)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide (Intermediate 101)

[0698] In accordance with the procedures for synthesis of Intermediate20 the above-identified compound (2.29 g) was obtained from Intermediate100 (1.78 g) by reaction and after-treatment.

[0699] C. Synthesis of (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 102)

[0700] In accordance with the procedures for synthesis of Intermediate21, the-above-identified compound (243.0 mg) was obtained fromIntermediate 101 (445 mg) and Intermediate 2 (294 mg) by reaction andafter-treatment. Rf=0.50 (methanol/chloroform of 1/10).

[0701] D. Synthesis of (R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0702] Intermediate 102 (243 mg) was dissolved in anhydroustetrahydrofuran (15 ml), whereto 4 N hydrogenchloride/1,4-dioxane (1 ml)was added and the mixture was agitated at room temperature for 1 hour.The deposited precipitate was taken out and washed with tetrahydrofuran,whereupon it was dried under a reduced pressure at 40° C., whereby theabove-identified compound was obtained (96.8 mg).

[0703] Retention time: 42.1 min. for R-modification (38.5 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.): mobile phase: 0.5M NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 78

[0704](S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0705] A. Synthesis of(S)-N-[5-(2-bromo-1-hydroxyethyl)-2-fluorophenyl]methanesulfonamide(Intermediate 103)

[0706] In accordance with the procedures of synthesis of Intermediate19, the above-identified compound (1.36 g) was obtained fromIntermediate 9 (1.53 g) using as the asymmetric catalyst an(S)-modification by reaction and after-treatment.

[0707] Retention time: (31.1 min. for R-modification) 33.3 min. forS-modification; Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (1/1); flow rate: 0.3 ml/min.; detection: 254 nm;temperature: R.T.

[0708] B. Synthesis of(S)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 104)

[0709] In accordance with the procedures for synthesis of Intermediate20 the above-identified compound (1.85 g) was obtained from Intermediate103 (1.36 g) by reaction and after-treatment.

[0710] C. Synthesis of (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-fluorophenyl]methanesulfonamide(Intermediate 105).

[0711] In accordance with the procedures for synthesis of Intermediate21, the above-identified compound (198.2 mg) was obtained fromIntermediate 104 (445 mg) and Intermediate 2 (294 mg) by reaction andafter-treatment.

[0712] D. Synthesis of(S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-fluorophenyl]methanesulfonamideHydrochloride

[0713] Intermediate 105 (154.8 mg) was dissolved in anhydroustetrahydrofuran (6.8 ml), whereto 4 N hydrogenchloride/1,4-dioxane (430μl) was added and the mixture was agitated at room temperature for 1hour. The deposited precipitate was taken out and was washed withtetrahydrofuran, whereupon it was dried under a reduced pressure at 40°C. whereby the above-identified compound was obtained (109.0 mg).

[0714] Retention time: (42.1 min. for R-modification) 38.5 min. forS-modification; Analytical condition: column: two sets. 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 79

[0715](R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0716] A. Synthesis of(R)-N-[5-(2-bromo-1-hydroxyethyl)-2-chlorophenyl]methanesulfonamide(Intermediate 106)

[0717] In accordance with the procedures of synthesis of Intermediate19, the above-identified compound (880 mg) was obtained fromIntermediate 13 (800 mg) by reaction and after-treatment.

[0718] Retention time: 14.1 min. for R-modification (16.8 min. forS-modification); Analytical condition: column: 4.6 mm ID×250 mm,CHIRALPAK AD (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane (4/1): flow rate: 0.5 ml/min.; detection: 254 nm:temperature: R.T.

[0719] B. Synthesis of(R)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 107)

[0720] In accordance with the procedures for synthesis of Intermediate20, the above-identified compound (1.24 g) was obtained fromIntermediate 106 (880 mg) by reaction and after-treatment.

[0721] C. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 108)

[0722] In accordance with the procedures for synthesis of Intermediate21, the above-identified compound (135.9 mg) was obtained fromIntermediate 107 (489.4 mg) and Intermediate 2 (294 mg) by reaction andafter-treatment. Rf=0.57 (methanol/chloroform of 1/10).

[0723] D. Synthesis of(R)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0724] Intermediate 108 (73.2 mg) was dissolved in anhydroustetrahydrofuran (4.2 ml), whereto 4 N hydrogenchloride/1,4-dioxane (240A l) was added and the mixture was agitated at room temperature for 1hour. The deposited precipitate was taken out and washed withtetrahydrofuran, whereupon it was dried under a redueced pressure at 40°C., whereby the above-identified compound was obtained (36.3 mg).

[0725] Retention time: 61.7 min. for R-modification (58.4 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R(supplied from Daicel Chem. Ind.); mobile phase: 0.5 MNaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate: 0.5ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 80

[0726](S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0727] A. Synthesis of(S)-N-[5-(2-bromo-1-hydroxyethyl)-2-chlorophenyl]methanesulfonamide(Intermediate 109) In accordance with the procedures of synthesis ofIntermediate 19, the above-identified compound (753.4 mg) was obtainedfrom Intermediate 13 (780 mg) using as the asymmetric catalyst an(S)-modification by reaction and after-treatment.

[0728] Retention time: (14.1 min. for R-modification) 16.8 min. forS-modification; Analytical condition: column: 4.6 mm ID×250 mm.CHIRALPAK AD (supplied from Daicel Chem. Ind.); mobile phase:ethanol/n-hexane 4/1); flow rate: 0.5 ml/min.; detection: 254 nm:temperature: R.T.

[0729] B. Synthesis of (S)-N-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide (Intermediate 110)

[0730] In accordance with the procedures for synthesis of Intermediate20 the above-identified compound (1.06 g) was obtained from Intermediate109 (753 mg) by reaction and after-treatment.

[0731] C. Synthesis of (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-chlorophenyl]methanesulfonamide(Intermediate 111)

[0732] In accordance with the procedures for synthesis of Intermediate21, the above-identified compound (111.2 mg) was obtained fromIntermediate 110 (490 mg) and Intermediate 2 (294 mg) by reaction andafter-treatment.

[0733] D. Synthesis of (S)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-chlorophenyl]methanesulfonamideHydrochloride

[0734] Intermediate 111 (111.2 mg) was dissolved in anhydroustetrahydrofuran (6.3 ml), whereto 4 N hydrogenchloride/1,4-dioxane (360μl) was added and the mixture was agitated at room temperature for 1hour. The deposited precipitate was taken out and washed withtetrahydrofuran, whereupon it was dried under a reduced pressure at 40°C., whereby the above-identified compound was obtained (70.4 mg).

[0735] Retention time: (61.7 min. for R-modification) 58.4 min. forS-modification: Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (7/3); flow rate:0.5 ml/min.; detection: 254 nm: temperature: 40° C.

EXAMPLE 81

[0736](R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamideHydrochloride

[0737] A. Synthesis of(R)-N-methyl-[5-(2-bromo-1-hydroxyethyl)-2-benzyloxy]benzenesulfonamide(Intermediate 112)

[0738] In accordance with the procedures of synthesis of Intermediate19, the above-identified compound (752.2 mg) was obtained fromIntermediate 81 (800 mg) by reaction and after-treatment. Rf=0.15 (ethylacetate/n-hexane of 1/2).

[0739] B. Synthesis of (R)-N-methyl-[5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]-2-benzyloxy]benzenesulfonamide (Intermediate 113)

[0740] In accordance with the procedures for synthesis of Intermediate20, the above-identified compound (587.9 mg) was obtained fromIntermediate 112 (462.8 mg) by reaction and after-treatment. Rf=0.53(ethyl acetate/n-hexane of 1/2).

[0741] C. Synthesis of (R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 114)

[0742] In accordance with the procedures for synthesis of Intermediate21, the above-identified compound (265.3 mg) was obtained fromIntermediate 113 (587.9 mg) and Intermediate 2 (295 mg) by reaction andafter-treatment. Rf=0.45 (methanol/chloroform of 1/10).

[0743] D. Synthesis of (R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide (Intermediate115)

[0744] To a solution of Intermediate 114 (265.3 mg) in 13.3 ml ofanhydrous tetrahydrofuran, acetic acid (169.6 μl) and 1 M solution (2.65ml) of tetrabutylammonium fluoride in tetrahydrofuran were added and themixture was agitated at room temperature for 1 hour. The reactionmixture was diluted with ethyl acetate and was washed with saturatedaqueous sodium bicarbonate solution and then with saturated aqueoussodium chloride solution, followed by drying over anhydrous sodiumsulfate, whereupon the solvent was distilled off under a reducedpressure. The resulting residue was triturated in ethanol, whereupon theabove-identified compound (111.3 mg) was obtained. On the other hand,the residue left after evaporation of the filtrate was purified by asilica gel chromatography (methanol/chloroform of 7/100), whereby theabove-identified compound was obtained (59 mg).

[0745] E. Synthesis of (R)-N-methyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamide Hydrochloride

[0746] In accordance with the procedure described in Example 2,Intermediate 115 (166.3 mg) was treated by reaction and after-treatment,whereby the above-identified compound (136.3 mg) was obtained.

[0747] Retention time: 117.8 min. for R-modification (132.6 min. forS-modification); Analytical condition: column: two sets, 4.6 mm ID×150mm, CHIRALCEL OJ-R (supplied from Daicel Chem. Ind.); mobile phase: 0.5M NaClO₄/HClO₄ buffer solution (pH 2.0)/acetonitrile (78/22); flow rate:0.5 ml/min.; detection: 254 nm; temperature: 40° C.

EXAMPLE 82

[0748](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamideHydrochloride

[0749] A. Synthesis of 1-(4-acetylamino-3-nitrophenyl)ethanone(Intermediate 116)

[0750] To 4.5 ml of ice-cooled acetic anhydride, 0.5 ml of fuming nitricacid was added in five allotted portions under agitation. Thereto wereadded dropwise a solution of 350 mg of 4-acetamid-acetophenone (suppliedfrom the firm Lancaster) in acetic acid (1.8 ml) over a period of 7minutes, while maintaining the temperature below 12° C. After agitationfor 38 minutes at 5° C., 10 ml of water and 10 ml of ethyl acetate wereadded thereto and the organic layer was separated. The aqueous layer wassubjected extraction with 10 ml of ethyl acetate and the organic layerswere united and the united organic phase was poured into 200 ml ofsaturated aqueous sodium bicarbonate solution and the mixture wasagitated for 30 minutes. The organic layer was separated and the aqueouslayer was subjected to extraction with 50 ml of ethyl acetate and theorganic layers were brought together and the so-united organic phase wasdried, followed by distilling off of the solvent, whereby 0.41 g of theabove-identified compound was obtained. Rf=0.67 (methanol/chloroform of1/19).

[0751] B. Synthesis of 1-(3-amino-4-acetylaminophenyl)ethanone(Intermediate 117)

[0752] To a solution of 410 mg of Intermediate 116 in 40 ml of methanol,20 mg of platinum oxide were added under argon atmosphere and thereaction system was replaced with hydrogen gas under ice-cooling. Themixture was agitated at room temperature for 12.5 hours, whereupon thereaction system was replaced with argon gas and 20 ml of chloroform wereintroduced into the reaction mixture. Catalyst was separated and thesolvent in the filtrate was distilled off under a reduced pressure. Theresulting residue was purified by a silica gel chromatography (elutedwith ethyl acetate/n-hexane of 3/7—solely with ethyl acetate), whereby0.29 g of the above-identified compound was obtained. Rf=0.06(methanol/chloroform of 1/19).

[0753] C. Synthesis of 1-[4-acetylamino-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate 118)

[0754] According to the method reported by A. A. Larsen et al in J. Med.Chem., 10, 462-472 (1967), the above-identified compound was preparedfrom Intermediate 117 (290 mg) and methanesulfonyl chloride (118.5 μl).Here, however, a modification in the purification of the reactionmixture was incorporated such that the reaction was terminated withaddition of 10 ml of water with adjustment of pH at 4 by 1 Nhydrochloric acid, before extraction with ethyl acetate (4 times eachwith 30 ml). The organic layer was washed with saturated aqueous sodiumchloride solution and dried, whereupon the solvent was distilled offunder a reduced pressure. By purifying the resulting residue by a silicagel chromatography (methanol/chloroform of 3/97), 315 mg of theabove-identified compound were obtained. Rf=0.37 (methanol/chloroform of1/19).

[0755] D. Synthesis of 2-bromo-1-[4-acetylamino-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate 119)

[0756] In the same manner as the procedures described in the step A ofExample 29 except that the purification of the compound from thereaction mixture was performed only by a silica gel chromatography(elution with ethyl acetate/n-hexane of 7/13—with ethyl acetate only),267 mg of the above-identified compound were obtained from 310 mg ofIntermediate 118and 570 mg of cupric bromide. Rf=0.68 (ethylacetate/n-hexane of 1/1).

[0757] E. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-acetylaminophenyl]methanesulfonamide(Intermediate 120)

[0758] In the same manner as the procedures described in the step D ofExample 1 except that only a silica gel chromatography(methanol/chloroform of 5/95-15/85) was employed for purifying the crudeproduct, the above-identified compound (53 mg) was synthesized fromIntermediate 119 (147 mg) and Intermediate 2 (90.5 mg). Rf=0.17(methanol/chloroform of 1/9).

[0759] F. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-aminophenyl]methanesulfonamideHydrochloride

[0760] 70 mg of Intermediate 120 were added to 8 ml of 1.4-dioxane andthereto were added 2 ml of concentrated hydrochloric acid, whereupon toreaction mixture was agitated for 1 hour with heating under reflux. Themixture was evaporated to dryness under a reduced pressure and theresulting residue (60 mg) was processed by recrystallization frommethanol/ethyl acetate, whereby 13 mg of the above-identified compoundwere obtained. Rf=0.05 (water/methanol/chloroform of 1/15/25).

EXAMPLE 83

[0761] (±)-N-methyl-N-benzyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxylbenzenesulfonamideHydrochloride

[0762] A. Synthesis of N-methyl-N-benzyl-(2-benzyloxy-5-acetyl)benzenesulfonamide (Intermediate 121)

[0763] In the same manner as the procedures described in the step A ofExample 65, the above-identified compound was prepared from1-(3-amino-4-benzyloxy-phenyl)ethanone. Here, however, instead of adding40% aqueous solution of methylamine, 0.2 ml of N-methyl-benzylamine and0.7 ml of triethylamine were reacted in 10 ml of dichloromethane for31.5 hours. To the reaction mixture, 10 ml of water were added and theorganic layer was collected. The organic layer was washed with 1 Nhydrochloric acid and saturated aqueous sodium chloride solution,followed by drying. whereupon the solvent was distilled off under areduced pressure, whereby 398 mg of the above-identified compound wereobtained. Rf=0.36 (ethyl acetate/n-hexane of 1/2).

[0764] B. Synthesis ofN-methyl-N-benzyl-[2-benzyloxy-5-(2-bromoacetyl)]benzenesulfonamide(Intermediate 122)

[0765] In the same manner as the procedures described in the step A ofExample 29 except that the purification was effected by a silica gelchromatography (ethyl acetate/n-hexane of 1/9-1/4) the above-identifiedcompound (228 mg) was produced from Intermediate 121 (205 mg) and cupricbromide (246 mg). Rf=0.50 (ethyl acetate/n-hexane of 1/2).

[0766] C. Synthesis of(±)-N-methyl-N-benzyl-[5-[2-[2-(9H-carbnazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]benzenesulfonamide(Intermediate 123)

[0767] According to the procedures described in the step D of Example 1except that a silica gel chromatography (elution withmethanol/chloroform of 5/95 for the first and with methanol/ethylacetate of 1/19 for the second elution) was employed for thepurification of crude product, the above-identified compound (0.20 g)was obtained from Intermediate 122 (228 mg) and Intermediate 2 (102 mg).Rf=0.25(methanol/chloroform of 1/19).

[0768] D. Synthesis of(±)-N-methyl-N-benzyl-[5-[2-(2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamideHydrochloride

[0769] According to the procedures described in Example 2, 0.20 g ofIntermediate 123 were subjected to a hydrogenolysis for 1 hour using 100mg of 10% palladium/carbon black, followed by conversion intohydrochloride salt and recrystallization from methanol/ethyl acetate,whereby 62 mg of the above-identified compound were obtained. Rf=0.31(methanol/chloroform of 1/9).

EXAMPLE 84

[0770](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl]methanesulfonamide

[0771] A. Synthesis of1-[4-(ethoxycarbonyl)phenyl]ethanone-ethyleneacetal (Intermediate 124)

[0772] 9.61 g of 4-acetylbenzoic acid ethyl ester (supplied from thefirm Wako Pure Chem. Ind.) were dissolved in 200 ml of toluene andthereto were added 20 ml of ethylene glycol and 200 mg ofp-toluenesulfonic acid hydrate under argon atmosphere, whereupon themixture was heated under reflux for 24 hours on Dean-Stark apparatuswhile removing water. The reaction mixture was then cooled down to roomtemperature and the toluene layer was washed with water (twice with each100 ml) and, then, with saturated aqueous sodium chloride solution (100ml), followed by drying and evaporation to dryness under a reducedpressure, whereby the above-identified compound (12.76 g) was obtained.Rf=0.58 (ethyl acetate/n-hexane of 1/2).

[0773] B. Synthesis of 1-[4-(hydroxymethyl)phenyl]ethanone (Intermediate125)

[0774] 1.90 g of lithium aluminum hydride were suspended in 120 ml ofanhydrous tetrahydrofuran under argon atmosphere and thereto were addeddropwise a solution of 12.76 g of Intermediate 124 in 40 ml of anhydroustetrahydrofuran over a period of 90 minutes under ice-cooling withsubsequent agitation for 90 minutes. Thereto were added 100 ml of ethylacetate gradually over a period of 25 minutes to terminate the reaction,whereupon 100 ml of 1 N sulfuric acid were added thereto over a periodof 30 minutes. The mixture was further agitated at room temperature for45 minutes, whereupon 100 ml of water were added thereto and the organicphase was collected. The aqueous phase was subjected to extraction withethyl acetate (twice with each 100 ml) and the organic layers werebrought together and the so-united organic phase was washed with water(100 ml) and, then, with saturated aqueous sodium chloride solution (100ml), followed by drying and distilling off of the solvent under areduced pressure. The resulting residue (12.25 g) was dissolved inacetone (200 ml), whereto p-toluenesulfonic acid hydrate (200 mg) wasadded and the mixture was agitated for 20 hours at room temperature,After confirmation of termination of the reaction by 1H-NMR, the acetonesolvent was distilled off under a reduced pressure. The residue wastreated by partition between 50 ml of ethyl acetate and 50 ml of waterand the organic layer was separated, which was washed with saturatedaqueous sodium chloride solution and dried, before the solvent wasdistilled off under a reduced pressure, whereby 6.688 g of theabove-identified compound were obtained. Rf=0.19 (ethyl acetate/n-hexaneof 1/2).

[0775] C. Synthesis of 1-[4(acetoxymethyl)phenyl]ethanone (Intermediate126)

[0776] 6.67 g of Intermediate 125 were dissolved in 7.3 ml of pyridineand thereto were added 6.3 ml of acetic anhydride, whereupon the mixturewas agitated at room temperature for 12.5 hours. Thereto were added 300ml of water to terminate the reaction and the mixture was subjected toextraction with 50 ml of ethyl acetate. The aqeous layer was treated byextraction with ethyl acetate (twice with each 50 ml) and the organiclayers were brought together, whereupon the so-united organic phase waswashed with 100 ml of water, 50 ml of 1 N hydrochloric acid and,finally, 50 ml of saturated aqueous sodium chloride solution,successively, followed by drying and evaporation of the solvent under areduced pressure, whereby 8.27 g of the above-identified compound wereobtained. Rf=0.56 (ethyl acetate/n-hexane of 1/1).

[0777] D. Synthesis of 1-[3-nitro-4-(acetoxymethyl)phenyl]ethanone(Intermediate 127)

[0778] To 80 ml of fuming nitric acid under cooling with an ice/saltcoolant, 8.09 g of Intermediate 126 were added all at once. Whilemaintaining this temperature, the mixture was agitated for 10 minutes,before it was poured into 300 ml of ice/water mixture. This was treatedby extraction with ethyl acetate (three times with each 80 ml) and theorganic layer was washed with water (three times with each 100 ml), withsaturated aqueous sodium bicarbonate solution and with saturated aqueoussodium chloride solution, successively, with subsequent drying,whereupon the solvent was distilled off under a reduced pressure. Theresulting residue (9.70 g) was purified by a silica gel chromatography(ethyl acetate/n-hexane of 1/2), whereby 8.41 g of the above-identifiedcompound were obtained. Rf=0.36 (ethyl acetate/n-hexane of 1/2).

[0779] E. Synthesis of 1-[3-amino-4-(acetoxymethyl)phenyl]ethanone(intermediate 128)

[0780] 1.97 g of Intermediate 127 were dissolved in 358 ml of methanoland thereto were added 10.55 g of stannous chloride and 7.5 ml ofconcentrated hydrochloric acid under argon atmosphere, whereupon themixture was agitated at room temperature for 2 hours. Thereto were added200 ml of saturated aqueous sodium bicarbonate solution and the mixturewas agitated at room temperature for 75 minutes, whereupon the inorganicsalts precipitated were removed by filtering on celite and the filtratewas evaporated under a reduced pressure to a volume of about 200 ml.This was subjected to extraction with ethyl acetate (300 ml) and theextract was washed with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue (1.32 g) was purified by asilica gel chromatography (ethyl acetate/n-hexane of 1/2), whereby 0.56g of the above-identified compound was obtained. Rf=0.31 (ethylacetate/n-hexane of 1/2).

[0781] F. Synthesis of 1-[3-(methylsulfonyl)amino-4-(acetoxymethyl)phenyl]ethanone (Intermediate 129)

[0782] 0.56 g of Intermediate 128 was dissolved in 3.6 ml of pyridineand thereto were added 215 μl of methanesulfonyl chloride under argonatmosphere and the mixture was agitated at room temperature for 26hours. Thereto were added 5 ml of water and the mixture was subjected toextraction with ethyl acetate (three times with each 20 ml) and theorganic layer was washed with 1 N hydrochloric acid (twice with each 50ml) and saturated aqueous sodium chloride solution, successively, withsubsequent drying, whereupon the solvent was distilled off under areduced pressure, whereby 0.58 g of the above-identified compound wasobtained. Rf=0.39 (ethyl acetate/n-hexane of 1/1).

[0783] G. Synthesis of2-bromo-1-[3-(methylsulfonyl)amino-4-(acetoxymethyl)phenyl]ethanone(Intermediate 130)

[0784] In the same manner as the procedures described in the step A ofExample 29, the above-identified compound (430 mg) was produced fromIntermediate 129 (285 mg) and cupric bromide (491 mg, supplied fromKanto Chem. Co., Inc.). Rf=0.44 (ethyl acetate/n-hexane of 1/2).

[0785] H. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-(acetoxymethyl)phenyl]-methanesulfonamide(intermediate 131)

[0786] According to the procedures described in the step D of Example 1except that a silica gel chromatography (with methanol/ethyl acetate of1/9-1/4 for the first and with 10% conc. aq. ammonia-containingmethanol/chloroform of 2/25 for the second) was employed for thepurification of the crude product, the above-identified compound (68 mg)was obtained from Intermediate 130 (405 mg) and Intermediate 2 (226 mg).Rf=0.18(10% conc. aq. ammonia-containing methanol/chloroform of 1/9).

[0787] I. Synthesis of(±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenyl]-methanesulfonamideHydrochloride

[0788] To 68 mg of Intermediate 131, 10 ml of 2 N aqueous sodiumhydroxide solution were added and the mixture was agitated at roomtemperature for 2.5 hours. This was diluted with 30 ml of water andthereto were added 50 ml of saturated aqueous sodium chloride solution,followed by extraction with ethyl acetate(three times with each 50 ml).The organic layer was dried and the solvent was distilled off therefromunder a reduced pressure, whereupon the resulting residue was purifiedby a silica gel chromatography (10% conc. aq. ammonia-containingmethanol/ethyl acetate of 1/9), whereby free base product of theabove-identified compound was obtained. This was converted intohydrochloride salt by a usual technique, which was then treated bycrystallization from methanol/ethyl acetate to obtain 22 mg of theabove-identified compound. Rf=0.11 (10% conc. aq. ammonia-containingmethanol/chloroform of 1/9).

EXAMPLE 85

[0789](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamide

[0790] 2-bromo-1-[4-bromo-3-[(methylsulfonyl)amino]phenyl]ethanone wasproduced in the same manner as in the steps B, C and D of Example 6 inaccordance with the procedures for the synthesis of Intermediate 13.

[0791] A. Synthesis of 1-(3-amino-4-bromophenyl)ethanone

[0792] To a solution of 5.0 g of 4-bromo-3-nitroacetophenone (suppliedfrom the firm Lancaster) in 890 ml of methanol, 19.4 g of tin (II)chloride and 17 ml of concentrated hydrochloric acid were added and themixture was agitated at room temperature for 3.5 hours. There to wereadded 470 ml of saturated aqueous sodium bicarbonate solution and thedeposited precipitate was filtered off, which was subjected toextraction with ethyl acetate. The organic layer was dried andconcentrated under a reduced pressure, whereby 3.97 g of theabove-identified compound were obtained. Rf=0.43 (ethyl acetate/n-hexaneof 1/2).

[0793] B. Synthesis of 1-[4-bromo-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate 132)

[0794] To a solution of 3.97 g of the above compound in 21 ml ofpyridine, 1.8 ml of methanesulfonyl chloride were added at roomtemperature and the mixture was agitated for 1 hour. The mixture waspoured into 142 ml of water. After agitation overnight, the depositedprecipitate was isolated by filtration and was dissolved in ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride solution with subsequent drying, and concentrated under areduced pressure to obtain a crude product (4.08 g). Rf=0.41 (ethylacetate/n-hexane of 1/1).

[0795] C. Synthesis of 2-bromo-1-[4-bromo-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate 133)

[0796] To a solution of 4.08 g of Intermediate 132 in 40 ml of1,4-dioxane, 0.75 ml of bromine was added with agitation under argonatmosphere. The resulting mixture was warmed to 60*C and was agitatedfor 1.5 hours. After having been cooled to room temperature, water wasadded. The mixture was extracted with ethyl acetate, organic layer waswashed with saturated aqeous sodium chloride solution and dried. Themixture was concentrated under a reduced pressure to obtain a crudeproduct (6.28 g). To this, a 1/1 liquid mixture of ethylacetate/n-hexane was added and warmed and cooled and the depositedprecipitate was isolated by filtration, whereby 4.0 g of theabove-identified compound were obtained. Rf=0.54 (ethyl acetate/n-hexaneof 1/1).

[0797] D. Synthesis of (±)-[5-(2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-bromophenyl]methanesulfonamideHydrochloride

[0798] According to the procedures described in the step D of Example 1,a free amine product of the above-identified compound (191.6 mg) wasproduced from HBr-addition salt of Intermediate 2 (452.5 mg) andIntermediate 133 (742.1 mg) through reaction and after-treatment withsubsequent purification by a PTLC (with development bymethanol/chloroform of 1/10). Rf=0.58 (methanol/ethyl acetate of 1/3).

[0799] This was converted into its hydrochloride salt (theabove-identified compound) by adding thereto 1.1 equivalent amount of0.1 N hydrogen chloride/ethanol, wherefrom the solvent was distilled offunder a reduced pressure. To the resulting residue, diethyl ether wasadded and the deposited precipitate was collected by filtration and wasprocessed by recrystallization from ethanol, followed by drying at 50°C. under a reduced pressure, whereby the above-identified compound(112.6 mg) was obtained as a powdery product.

EXAMPLE 86

[0800](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamide

[0801] 2-bromo-1-[4-iodo-3-[(methylsulfonyl)amino]phenyl]ethanone wasproduced in the same manner as in the steps A, B, C and D of Example 6.

[0802] A. Synthesis of 1-(4-iodo-3-nitrophenyl)ethanone (Intermediate134)

[0803] 20 g of 4′-iodoacetophenone (Tokyo Chemical Industry Co., Ltd.)were added in two portions to 130 ml of fuming nitric acid cooled withice/salt. After agitation for 15 minutes, the resulting mixture waspoured into 1 liter of ice water and was then subjected to extractionwith 1 liter of ethyl acetate. The organic layer was separated and driedand the solvent was evaporated off, whereby 20.7 g of theabove-identified compound were obtained. Rf=0.19 (ethyl acetate/n-hexaneof 1/5).

[0804] B. Synthesis of 1-(3-amino-4-iodophenyl)ethanone (Intermediate135)

[0805] To a solution of 14.3 g of Intermediate 134 in 2134 ml ofmethanol, 40.5 g of tin (It) chloride and 40.8 ml of concentratedhydrochloric acid were added and the mixture was agitated at roomtemperature for 4.75 hours. To this mixture, 1100 ml of saturatedaqueous sodium bicarbonate solution were added and deposited precipitatewas separated by filtration. Filtrate was partly concentrated and wassubjected to extraction with ethyl acetate. The organic layer was driedand concentrated to dryness under a reduced pressure, whereby 11.87 g ofthe above-identified compound were obtained. Rf=0.67(methanol/chloroform of 1/10).

[0806] C. Synthesis of1-[4-iodo-3-[(methylsulfonyl)amino]phenyl]ethanone (intermediate 136)

[0807] To a solution of 11.87 g of the Intermediate 135 in 50 ml ofpyridine. 3.55 ml of methanesulfonyl chloride were added at roomtemperature. After agitation for 2.5 hours, the reaction mixture waspoured into water (250 ml). The deposited precipitate was separated byfiltration and dissolved in ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride solution and dehydrated andconcentrated under a reduced pressure to obtain a crude product. Tothis, ethyl acetate/n-hexane (1/1) was added and deposited precipitatewas recovered by filtration and drying, whereby 10.44 g theabove-identified compound were obtained. Rf=0.14 (ethyl acetate/n-hexaneof 1/3).

[0808] D. Synthesis of2-bromo-1-[4-iodo-3-[(methylsulfonyl)amino]phenyl]ethanone (Intermediate137)

[0809] To a solution of 10.4 g of Intermediate 136 in 102 ml of1.4-dioxane. 1.66 ml of bromine were added under argon atmosphere withagitation. The resulting mixture was warmed to 60° C. and was agitatedfor 1.5 hours. After having been cooled to room temperature, it wasprocessed by extraction of water and ethyl acetate, washing of theorganic layer, drying and evaporating under reduced pressure, whereby11.77 g of the above-identified compound were obtained. Rf=0.25 (ethylacetate/n-hexane of 1/2).

[0810] E. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-iodophenyl]methanesulfonamideHydrochloride

[0811] According to the procedures described in the step D of Example 1,free amine product of the above-identified compound (211.5 mg) wasobtained, from Intermediate 2 (500 mg) and Intermediate 137 (1.385 g) byreaction and after-treatment through crude purification of the resultingresidue on a column chromatography (6.3% methanol/chloroform) and finepurification by a PTLC (development with 10% conc. aq.ammonia-containing methanol/ethyl acetate of 1/4). Rf=0.49 (10% conc.aq. ammonia-containing methanol/ethylacetate of 1/4).

[0812] To this product, 1.1 equivalent amount of 0.1 N hydrochloricacid/ethanol were added to convert it into hydrochloride salt (theabove-identified compound) and the solvent was distilled off under areduced pressure. After drying at 50° C. under reduced pressure 218 mgof the above-identified compound were obtained as a powdery product.

EXAMPLE 87

[0813](±)-N′-[5-[2-(2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-methyl-N-benzylsulfamideHydrochloride

[0814] A. Synthesis of N-methyl-N-benzylsulfamoyl Chloride

[0815] To an ice-cooled solution of 3.0 ml of sulfurylchloride in 50 mlof dichloromethane under argon atmosphere, 6.45 ml ofN-methyl-N-benzylamine and 7.0 ml of triethylamine were added over aperiod of 15 minutes. After agitation for 15 minutes, 50 ml of water wasadded thereto to terminate the reaction. The organic layer was separatedand washed with 50 ml of 1 N hydrochloric acid with subsequent drying,whereupon the solvent was distilled off under a reduced pressure. 100 mlof n-hexane were added to the resulting residue (8.35 g) and the mixturewas cooled, whereupon the deposited precipitate was filtered off. Thefiltrate was evaporated to dryness under a reduced pressure, whereby5.30 g of the above-identified compound were obtained. Rf=0.64 (ethylacetate/n-hexane of 1/4).

[0816] B. Synthesis of 1-[4-benzyloxy-3-[(N-methyl-N-benzylsulfamoyl)amino]phenyl]ethanone (Intermediate 138)

[0817] The above-identified compound (671 mg) was produced from theabove Intermediate (880 mg) and 1-(3-amino-4-benzyloxyphenyl)ethanone(482 mg) [this was carried out in accordance with the method reported byA. A. Larsen et al in J. Med. Chem., 10, 462-472(1967)]. Here, however,a mixed solvent of pyridine/dichloromethane (7 ml, 2/5) was used andthere action mixture was agitated first at room temperature for 66 hoursand, then, agitated with heating under reflux for further 2 hours. Thepurification was performed by extraction with 20 ml of water and 50 mlof ethyl acetate and washing the organic layer with 30 ml of 1 Nhydrochloric acid. The united aqueous phase was extracted further withethyl acetate (twice with each 30 ml), whereupon the united organicphase was washed with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was purified by a silica gelchromatography (ethyl acetate/n-hexane of 1/3). Rf=0.47(methanol/chloroform of 1/19).

[0818] C. Synthesis of2-bromo-1-[4-benzyloxy-3-[(N-methyl-N-benzylsulfamoyl)amino]phenyl]ethanone(Intermediate 139)

[0819] In the same manner as the procedures described in the step A ofExample 29, the above-identified compound (810 mg, ca. 80% purity) wasproduced from Intermediate 138 (670 mg) and cupric bromide (780 mg).Rf=0.41 (ethyl acetate/n-hexane of 1/2).

[0820] D. Synthesis of(±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N-methyl-N-benzylsulfamide(Intermediate 140)

[0821] The above-identified compound (251 mg) was produced throughreaction and after-treatment in accordance with the procedures describedin the step D of Example 1 from Intermediate 2 (400 mg), triethylamine(280 μl) and Intermediate 139 (805 mg) via purification by a silica gelchromatography (elution with methanol/ethyl acetate of 1/9). Rf=0.47(methanol/chloroform of 1/9).

[0822] E. Synthesis of(±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N-methyl-N-benzylsulfamidehydrochloride

[0823] The above-identified compound (46 mg) was produced in accordancewith the procedures described in Example 2, by adding 250 mg ofIntermediate 140 to 50 ml of methanol and effecting a hydrogenolysisusing 122 mg of 10% palladium/carbon black with subsequent conversioninto hydrochloride salt by a usual method and recrystallization frommethanol/ethyl acetate. Rf=0.33 (methanol/chloroform of 1/9).

EXAMPLE 88

[0824](±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamideHydrochloride

[0825] A. Synthesis of N,N-diethylsulfamoyl Chloride

[0826] In accordance with the procedures decribed in the step A ofExample 87, 2.07 ml of N,N-diethylamine and 2.8 ml of triethylamine wereadded to an ice-cooled solution of 1.6 ml off sulfuryl chloride in 20 mlof dichloromethane, over a period of 2 hours under argon atmosphere.After agitation for 1 hour, 20 ml of water was added thereto toterminate the reaction. The organic layer was separated and washed with20 ml of 1 N hydrochloric acid with subsequent drying, whereupon thesolvent was distilled off under a reduced pressure. 30 ml of n-hexanewere added to the resulting residue and the mixture was cooled,whereupon the deposited precipitate was filtered off. The filtrate wasevaporated to dryness under a reduced pressure, whereby 2.19 g of theabove-identified compound were obtained. Rf=0.59 (ethyl acetate/n-hexaneof 1/4).

[0827] B. Synthesis of 1-[4-benzyloxy-3-[(N,N-diethylsulfamoyl)amino]phenyl]ethanone (intermediate 141)

[0828] The above-identified compound (513 mg) was produced from theabove Intermediate (686 mg) and 1-(3-amino-4-benzyloxyphenyl)ethanone(482 mg) [this was carried out in accordance with the method reported byA. A. Larsen et al in J. Med. Chem., 10, 462-472(1967)]. Here, however,a mixed solvent of pyridine/dichloromethane (7 ml, 2/5) was used and thereaction mixture was agitated first at room temperature for 66 hoursand, then, agitated with heating under reflux for further 2 hours. Thepurification was performed by extraction with 20 ml of water and 20 mlof ethyl acetate and washing the organic layer with 30 ml of 1 Nhydrochloric acid. The united aqueous phase was extracted further withethyl acetate (twice with each 30 ml), whereupon the united organicphase was washed with saturated aqueous sodium chloride solution withsubsequent drying, whereupon the solvent was distilled off under areduced pressure. The resulting residue was purified by a silica gelchromatography (ethyl acetate/n-hexane of 1/3). Rf=0.42 (ethylacetate/n-hexane of 1/2).

[0829] C. Synthesis of2-bromo-1-[4-benzyloxy-3-[(N,N-diethylsulfamoyl)amino]phenyl]ethanone(Intermediate 142) In the same manner as the procedures described in thestep A of Example 29, the above-identified compound (693 mg, ca. 70%purity) was produced from Intermediate 141 (500 mg) and cupric bromide(670 mg). Rf=0.64 (ethyl acetate/n-hexane of 1/2).

[0830] D. Synthesis of(±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-(benzyloxy)phenyl]-N,N-diethylsulfamide(Intermediate 143)

[0831] The above-identified compound (256 mg) was produced throughreaction and after-treatment in accordance with the procedures describedin the step D of Example 1 from Intermediate 2 (390 mg), triethylamine(28011) and Intermediate 142 (673 mg) via purification by a silica gelchromatography (elution with methanol/ethyl acetate of 1/9). Rf=0.46(methanol/chloroform of 1/9).

[0832] E. Synthesis of(±)-N′-[5-[2-[2-(9H-carbazol-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-diethylsulfamideHydrochloride

[0833] The above-identified compound (85 mg) was produced in accordancewith the procedures described in Example 2, by adding 250 mg ofIntermediate 143 to 50 ml of methanol and effecting a hydrogenolysisusing 120 mg of 10% palladium/carbon black with subsequent conversioninto hydrochloride salt by a usual method and recrystallization frommethanol/ethyl acetate. Rf=0.32 (methanol/chloroform of 1/9).

EXAMPLE 89

[0834](±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]benzenesulfonamideHydrochloride

[0835] A. Synthesis of N,N-dimethyl-[2-benzyloxy-5-(2-bromoacetyl)benzene]sulfonamide (Intermediate 144) In the same manner as theprocedures described in the steps A and B of Example 83, theabove-identified compound (705 mg) was prepared from1-(3-amino-4-benzyloxyphenyl)ethanone [prepared by the method reportedby A. A. Larsen et al in J. Med. Chem. 10, 462-472 (1967)]. Here,however, instead of adding N-methylbenzylamine. N,N-dimethylamine wasreacted. Rf=0.33 (ethyl acetate/n-hexane of 1/2).

[0836] B. Synthesis ofN,N-dimethyl-[2-benzyloxy-5-[2-iodo-1-[(triethylsilyl)oxy]ethyl]]benzenesulfonamide(Intermediate 145)

[0837] In the same manner as the procedures for the synthesis ofIntermediate 42, 700 mg of Intermediate 144 were treated by reaction andafter-treatment, whereby 407 mg of the above-identified compound wereobtained. Rf=0.74 (ethyl acetate/n-hexane of 1/1).

[0838] C. Synthesis of(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-[(triethylsilyl)oxy]ethyl]-2-benzyloxy]benzenesulfonamide(intermediate 146)

[0839] According to the procedures for the synthesis of Intermediate 43except that a silica gel chromatography (elution withmethanol/chloroform of 1/25) was employed for the purification of crudeproduct, the above-identified compound (138 mg) was obtained fromIntermediate 145 (398 mg) and Intermediate 2 (193 mg).Rf=0.43(methanol/chloroform of 1/10).

[0840] D. Synthesis of(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-benzyloxy]-benzenesulfonamide(Intermediate 147)

[0841] 135 mg of Intermediate 146 were dissolved in 7 ml of anhydroustetrahydrofuran, whereto 38.2 Al of acetic acid and 314 μl of 1 Msolution of tetrabutylammonium fluoride/tetrahydrofuran were added andthe mixture was agitated at room temperature for 14.5 hours. Then, themixture was diluted with ethyl acetate, followed by rinsing withsaturated aqueous sodium chloride solution and dried, whereupon thesolvent was distilled off under a reduced pressure. The residue waspurified by a PTLC (development with methanol/chloroform of 1/10),whereby 4.9 mg of the above-identified compound were obtained. Rf=0.23(methanol/chloroform of 1/10). By a usual technique, it was convertedinto hydrochloride salt (7.7 mg).

[0842] E. Synthesis of(±)-N,N-dimethyl-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxy]-benzenesulfonamideHydrochloride

[0843] The above-identified compound (5.0 mg) was produced in accordancewith the procedures described in Example 2, by performing ahydrogenolysis of Intermediate 147 (7.7 mg) using of 10%palladium/carbon black (4 mg) for 2 hours, followed by filtering off thecatalyst and distilling off the solvent under a reduced pressure.Rf=0.31 (methanol/chloroform of 1/9).

EXAMPLE 90

[0844](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0845] A. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-benzyloxyphenyl]methanesulfonamide(Intermediate 148)

[0846] 120 mg of the compound of Example 1 were agitated with heatingunder reflux in 10 ml of 10% hydrogen chloride/methanol for 24 hours.Then, the mixture was further agitated for 3 days at room temperature.The reaction mixture was evaporated to dryness under a reduced pressure,whereto saturated aqueous sodium bicarbonate solution was added andextraction with ethyl acetate was performed (twice with each 20 ml).After drying, evaporation was carried out and the residue was purifiedby a silica gel chromatography (methanol/chloroform of 1/19), whereby 72mg of the above-identified compound were obtained. Rf=0.55(methanol/chloroform of 1/9).

[0847] B. Synthesis of (±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamideHydrochloride

[0848] In accordance with the procedures described in Example 2, 70 mgof Intermediate 148 were subjected to hydrogenolysis using 30 mg of 10%palladium/carbon black for 1 hour, whereupon conversion intohydrochloride salt was effected with subsequent evaporation to drynessand trituration from diethyl ether, whereby 60 mg of theabove-identified compound were obtained. Rf=0.40 (methanol/chloroform of1/9).

EXAMPLE 91

[0849](±)-N-[5-[2-[2-(dibenzothiophen-3-yloxy)ethylamino]-1-methoxyethyl]-2-hydroxyphenyl]methanesulfonamidehydrochloride

[0850] 28 mg of the compound of Example 38 were suspended in 3 ml of 10%hydrogen chloride/methanol and the mixture was agitated for 3 days withheating under reflux. Then, 10 ml of 10% hydrogen chloride/methanol werereplenished thereto and the mixture was further agitated for 2 days. Thereaction mixture was evaporated to dryness under a reduced pressure andthe residue was dissolved in methanol and purified by a PTLC(development with methanol/chloroform of 1/10). From this, bytriturating in diethyl ether and filtration, 11.8 mg of theabove-identified compound were obtained. Rt=0.38 (methanol/chloroform of1/10).

EXAMPLE 92

[0851](±)-N-[5-[2-[2-(9H-carbazol-2-yloxy)ethylamino]-1-methoxyethyl]-2-aminophenyl]methanesulfonamideHydrochloride

[0852] Intermediate 120 (35 mg) was added to 10 v hydrogenchloride/methanol (5 ml) and the mixture was agitated for 2 hours withheating under reflux. By evaporating to dryness, the above-identifiedcompound (37 mg) was obtained. Rf=0.29 (methanol/chloroform of 1/9).

Test Example 1

[0853] Human β3-Agonist Activity:

[0854] Human 133-agonist activity was examined using CHO cells (chinesehamster ovarian cells) to which pcDNA3 (in vitrogen) cells insertedhuman β3 gene was transfected. Human β3 fragment was obtained by PCRusing human fat tissue cDNA (supplied from Clontech) with a β3 primer[Krief et al, J. Clin. Invest., Vol. 91, p344-349(1993)], And then fulllength of human β3 gene was cloned using this fragment as a probe.

[0855] The cells were cultured in a HAM F-12 medium containing 10% offetal bovine serum, 400 μg/ml of Geneticin (Gibco BRL). 100 U/mlpenicillin and 100 μg/ml streptomycin. 5×10⁵ cells were placed on a6-well plate and cultured for 24 hours, after which the medium waschanged to a HAM F-12 medium without serum and was kept for 2 hours.Each test compound was first dissolved in DMSO, and then diluted with aHAM F-12 medium containing 1 mM isobutylmethyl xanthine and 1 mMascorbic acid. A 10-fold dilution in the range of 10⁻⁵ to 10⁻¹² NM wasadded into the cell.

[0856] After culturing for 30 minutes, culture medium was withdrawn, 0.5ml of 1 N NaOH was added and was kept for 20 minutes. And then 0.5 ml of1 N acetic acid was added with subsequent agitation and centrifugation.Finally the concentration of cAMP were analyzed using cAMP EIA KIT(Cayman). intrinsic activities and ED₅₀ of 65 compounds in Example 1-92are shown in Table 2. BRL37344 was synthesized by the method given in“Drugs of the future”, Vol. 16, p 797-800 (1991). CL316, 243 wassynthesized by the method given in J. Med. Chem., Vol. 35, p 3081-3084.Isoprotelenol was purchased from Research Biochemicals International. Asseen in Table 2, the activities of these compounds were found to behigher than BRL 37344 and CL316,243.

Test Example 2

[0857] Effect on Heart:

[0858] The hearts of male guinea pigs having body weights in the rangeof 180-250 g were excised and each right atrium specimen was preparedwhich was set in an organ bath filled with aerated Krebs solution. Theautomaticity was measured using an isometric transducer (TB-611T of thefirm Nippon Koden) connected to a polygraph (NIR-6000 of the firm NipponKoden). The ED₅₀ values for the inventive compounds in Examples werehigher than that of β3 and these compounds have almost no contributionto increase in the cardiac rate, so that they are selective and areexpected to have lower side effects.

Test Example 3

[0859] Lipolytic Activity in Canine Fatty Cell:

[0860] Adipose tissues in the omentum were collected from dogs andminced and washed. Krebs-Ringer buffer solution containing 1 mg/mlCollagenase (Sigma) and 1% of bovine serum albumin was added in anamount of 3 ml per one grim of the tissue. These cells were thenincubated at 37° C. for 30 minutes with shaking and then undigestedtissues were removed with a nylon filter. The resulting adipocytes werewashed four times with Krebs-Ringer buffer, and then the concentrationof cells was diluted to 2×10⁵/ml with Krebs-Ringer buffer solutioncontaining 4% of bovine serum albumin. These cells were transfered toEppendorf tubes each in an amount of 300 μl.

[0861] Each 300 μl of a culture medium containing the test compoundswere added to these tubes and was held at 37° C. for 1 hour whithshaking. Stimulation was stoped by cooling with ice. Aftercentrifugation, the adipocytes were taken off with an aspirator,whereupon the glycerol was determined using F-KIT GLTCEROL(Behringer-Manheim). A shown in Table 3, the compounds of inventiveExamples exhibited in vitro lipolytic activities and, therfore, it wasexpected that they may be effective also in vivo lipolysis.

Test Example 4

[0862] Blood Sugar decreasing Effect and Lipolytic Effect:

[0863] Male ddy mice (supplied from the firm Nippon Charles Liver) of 6weeks age were subcutaneously administered with glucose in a dose of 2g/kg. The animals were also treated with either one of test compoundsvia oral or intraperitoneal administration in a dose of 0.1 ml per 10grams of body weight. After one hour, blood sample was taken fromabdominal aorta, from which serum was separated and served as thesample.

[0864] Blood Sugar decreasing Effect:

[0865] The samples prepared as above were analyzed for the serum glucoseconcentration by Auto analyzer (SUPER Z of the firm M.C. Medical). Forthe analyzer kit, Glucose II HA TEST WAKO (of the firm Wako PureChemical) was used.

% decrease in blood sugar=[(A−B)/(A−C)]×100 in

[0866] which A represents the glucose concentration upon being loadedwith glucose, B represents the glucose concentration afteradministration of the compound and C is the usual level of the glucoseconcentration.

[0867] The compound of Example 31 exhibited a blood sugar reduction ashigh as 34.5% by oral administration and the compound of Example 2showed a 77.1% reduction of blood sugar by intraperitonealadministration. Therefore, it was proven that the compound according tothe present invention is effective as a medicament for therapuetic andpreventive treatment of diabetes.

[0868] Lipolytic Effect:

[0869] Amount of free fatty acid in the samples was determined usingNEFA HA TEST WAKO (of the firm Wako Pure Chemical). The compounds ofExamples 31 and 7 have shown that they increaed 32.4% and 47.7% by anoral administration of 30 and 100 mg/kg, respectively. The compound ofExample 2 showed an increase of 67.2% by an intraperitonealadministration of 10 mg/kg. This shows that these compounds havelypolytic activity. Therefore, it was shown that they are useful asmedicament for preventive and therapeutic treatment of hyperlipemia andfor therapeutic treatment of obesity.

Test Example 5

[0870] Toxicity Test:

[0871] The compounds of Examples 7 and 31 were administered to 6 weekage male ddy mice (supplied from the firm Nippon Charles Liver) at adose of 100 mg/kg. For all 8 mice, no fatal case was found, which wasthe case for other compounds, so that the compound according to thepresent invention exhibit slow toxicity.

EFFECT OF THE INVENTION

[0872] The compounds according to the present invention are novel andare useful for use in drug composition for therapuetic and preventivetreatment of β3-correlating diseases, such as diabetes, obesity andhyperlipemia. TABLE 1 Compound No. 1H-NMR(CDCl₃): δ(ppm), J(Hz) MS m/zIntermed. 0 3.47(2H, t, J=6.0), 3.61(2H, q, J=6.0), 5.11(1H, s),5.29(1H, brs), 7.30˜7.38(5H, m) Intermed. 1 (DMSO-d6): 3.44(2H, bt),4.08 361 (2H, t, J=5.7), 5.05(2H, s), 6.76 (MH+) (1H, dd, J=2.1, 8.7),6.96(1H, bd, J=2.1), 7.10(1H, dd, J=7.3), 7.24˜7.38(6H, m), 7.41(1H, d,J=8.1), 7.52(1H, bt), 7.95 (1H, d, J=8.7), 7.97(1H, d, J=7.5), 11.08(1H,s) Intermed. 2 (DMSO-d6): 1.8˜2.1(2H, brs), 227 2.93(2H, t, J=5.8),4.00(2H, t, (MH+) J=5.8), 6.74(1H, dd, J=2.2, 8.5), 6.96(1H, d, J=2.2),7.10(1H, dd), 7.27(1H, dd), 7.41(1H, d, J=8.0), 7.95(1H, d, J=8.5),7.97(1H, d, J=7.7), 11.08(1H, s) Example 1 (DMSO-d6): 2.69(d, 2H, J=5.7)546 2.89(s. 3H), 2.96(t, 2H, J=5.2), (MH+) 4.09(t, 2H, J=5.2), 4.59(m,1H), 5.15(s, 2H), 5.31(bs, 1H), 6.76(dd, 1H, J=8.5, 2.2), 6.96 (d, 1H,J=1.9), 7.05˜7.17(m, 3H), 7.25˜7.42(m, 6H), 7.54(d, 2H, J=6.6), 7.96(t,2H, J=8.5), 11.08(s, 1H) Example 2 (DMSO-d6): 2.75(m, 2H), 2.93 456 (s,3H), 3.04(m, 2H), 4.14(t, 2H, (MH+) J=5.2), 4.60(m, 1H), 6.77(dd, 1H,J=8.8, 2.2), 6.85(d, 1H, J=8.2), 6.97(d, 1H, J=1.9), 7.04 (dd, 1H,J=8.2, 1.9), 7.10(m, 1H), 7.21(d, 1H, J=1.9), 7.28 (dt, 1H, J=8.0, 1.1),7.41(d, 1H, J=8.0), 7.97(m, 2H), 11.10 (s, 1H) Intermed. 4 3.66(q, 2H,J=5.2), 4.12(t, 2H, 362 J=5.2), 5.13(s, 2H), 5.27(bs, (MH+) 1H),6.91(dd, 1H, J=8.5, 2.2), 7.06(d, 1H, J=2.2), 7.26˜7.41 (m, 7H),7.52(dd, 1H, J=8.2, 0.8), 7.80(d, 1H, J=8.5), 7.85 (m, 1H) Intermed. 53.14(t, 2H, J=5.2), 4.09(t, 2H, 228 J=5.2), 6.96(dd, 1H, J=8.5, 2.2),(MH+) 7.10(d, 1H, J=2.2), 7.28˜7.41 (m, 2H), 7.52(m, 1H), 7.81 (d, 1H,J=8.5), 7.86(m, 1H) Example 3 (DMSO-d6): 2.71(d, 2H, J=5.5), 547 2.94(s,3H), 2.98(m, 2H), 4.14 (MH+) (m, 2H), 4.60(m, 1H), 5.13(bs, 1H), 5.16(s,2H), 5.31(bs, 1H), 7.00(dd, 1H, J=8.5, 2.4), 7.07 (d, 1H, J=8.5),7.15(dd, 1H, J=8.5, 2.2), 7.26˜7.48(m, 7H), 7.54(m, 2H), 7.64(dd, 1H,J=7.4, 0.8), 8.00(d, 1H, J=8.5), 8.04 (m, 1H) Example 4 (DMSO-d6):2.68(d, 2H, J=6.3), 457 2.92(s, 3H), 2.96(t, 2H, J=5.5), (MH+) 4.13(t,2H, J=5.5), 4.54(m, 1H), 6.83(d, 1H, J=8.2), 7.01 (septet, 2H), 7.19(d,1H, J=2.2), 7.30(d, 1H, J=2.2), 7.35 (dt, 1H, J=7.4, 1.1), 7.42(dt, 1H,J=7.4, 1.4), 7.64(d, 1H, J=8.0), 8.00(d, 1H, J=8.8), 8.03 (d, 1H, J=7.4)Intermed. 6 2.68(s, 3H), 7.42(dd, 1H, J=10.2, 8.4), 8.26(ddd, 1H, J=8.4,4.2, 2.1), 8.65(dd, 1H, J=7.2, 2.1) Intermed. 7 2.55(s, 3H), 3.88(bs,2H), 7.04 (ddd, 1H, J=10.5, 8.4, 0.6), 7.28˜7.35(m, 1H), 7.41(ddd, 1H,J=8.7, 2.1, 0.6) Intermed. 8 2.61(s, 3H), 3.09(s, 3H), 6.69 (bs, 1H),7.25(dd, 1H, J=9.9, 9.6), 7.82(ddd, 1H, J=8.4, 4.8, 2.1), 8.17(dd, 1H,J=7.5, 2.1) Intermed. 9 3.16(s, 3H), 4.41(s, 2H), 6.62 (bs, 1H), 7.28(t,1H, J=9.0), 7.86 (ddd, 1H, J=8.7, 4.8, 2.1), 8.21(dd, 1H, J=7.5, 2.1)Example 5 (DMSO-d6; HC1): 3.05(s, 3H), 3.13 458 (m, 1H), 3.31(m, 1H),3.49(m, (MH+) 2H), 4.38(m, 2H), 4.99(m, 2H), 6.31(d, 1H, J=4.2),6.84(dd, 1H, J=8.4, 2.4), 7.03(d, 1H, J=1.8), 7.12(m, 1H), 7.26˜7.38 (m,3H), 7.42˜7.50(m, 2H), 8.01 (m, 2H), 8.97(bs, 2H), 9.71 (m, 1H),11.19(s, 1H) Intermed. 10 2.65(s, 3H), 7.68(d, 1H, J=8.4), 8.09(dd, 1H,J=8.7, 2.1), 8.43 (d, 1H, J=2.1) Intermed. 11 2.55(s, 3H), 4.19(bs, 2H),7.23˜7.37 (m, 3H) Intermed. 12 2.61(s, 3H), 3.07(s, 3H), 6.86 (bs, 1H),7.54(d, 1H, J=8.4), 7.75 (dd, 1H, J=8.4, 2.1), 8.21 (d, 1H, J=2.1)Intermed. 13 3.10(s, 3H), 4.41(s, 2H), 6.90 (bs, 1H), 7.58(d, 1H,J=8.4), 7.78 (dd, 1H, J=8.4, 2.1), 8.24 (d, 1H, J=2.1) Example 6(DMSO-d6; HC1): 3.06(s, 3H), 3.17 474 (m, 1H), 3.27(m, 1H), 3.48(m,(NH+) 2H), 4.38(m, 2H), 5.00(m, 1H), 6.35(d, 1H, J=4.2), 6.84(dd, 1H,J=8.4, 2.7), 7.02(d, 1H, J=2.1), 7.12(m, 1H), 7.27˜7.34 (m, 2H), 7.44(d,1H, J=7.8), 7.52˜7.59 (m, 2H), 8.01(m, 2H), 8.91 (bs, 2H), 9.55(m, 1H),11.17 (s, 1H) Example 7 (DMSO-d6): 2.72(m, 2H), 2.96(s, 440 3H), 2.98(m,2H), 4.11(t, 2H, (NH+) J=5.7), 4.35(bs, 1H), 4.65(m, 1H), 5.40(bs, 1H),6.76(dd, 1H, J=8.5, 2.2), 6.96(d, 1H, J=1.9), 7.07˜7.13(m, 3H),7.24˜7.32 (m, 3H), 7.41(d, 1H, J=8.2), 7.96(m, 2H), 11.09(s, 1H)Intermed. 15 2.58(s, 3H), 4.36(s, 2H), 7.15 (bs, 1H), 7.22˜7.48(m, 6H),7.62˜7.75 (m, 2H), 8.57(m, 1H) Example 8 (DMSO-d6): 2.73(m, 2H), 2.98(m,516 2H), 4.11(m, 2H), 4.42(s, 2H), (NH+) 4.64(m, 1H), 5.38(m, 1H), 6.76(d, 1H, J=8.8), 6.96(s, 1H), 7.06˜7.13(m, 3H), 7.20˜7.46 (m, 9H),7.96(m, 2H), 11.09(s, 1H) Example 9 (DMSO-d6): 2.71(m, 2H), 2.96 441 (s,3H), 2.97(m, 2H), 4.14(m, 2H), (NH+) 4.63(m, 1H), 5.39(bs, 1H), 7.00(dd,1H, J=8.5, 2.2), 7.09 (m, 2H), 7.23˜7.46(m, 5H), 7.64 (d, 1H, J=7.4),8.02(m, 2H) Intermed. 17 2.20(s, 3H), 3.11(t, 2H, J=5.2), 3.84(s, 2H),4.04(t, 2H, J=5.2), 6.92(m, 1H), 7.08(m, 1H), 7.24˜7.38(m, 3H), 7.58(d,1H, J=2.2), 7.61(d, 1H, J=2.5), 7.83 (s, 1H) Example 10 (DMSO-d6):2.05(s, 3H), 2.71 496 (m, 2H), 2.94(s, 2H), 2.96(m, (NH+) 3H), 3.84(s,2H), 4.07(m, 2H), 4.63(m, 1H), 5.39(bs, 1H), 6.9 2(dd, 1H, J=8.5, 2.2),7.06˜7.15 (m, 3H), 7.24(s, 1H), 7.27(t, 1H, J=8.2), 7.46(d, 1H, J=8.2),7.65(d, 1H, J=2.7), 7.68(d, 1H, J=2.7), 7.86(s, 1H), 9.95 (s, 1H)Intermed. 18 (DMSO-d6): 1.10(d, 3H, J=6.3), 1.74(bs, 2H), 3.19(m, 1H),3.80 (m, 2H), 6.78(dd, 1H, J=8.5, 2.2), 6.97(d, 1H, J=1.9), 7.10 (t, 1H,J=7.4), 7.28(t, 1H, J=7.4), 7.42(d, 1H, J=8.0), 7.94(d, 1H, J=8.5),7.97(d, 1H, J=8.5), 11.16(s, 1H) Example 11 (DMSO-d6): 1.10(m, 3H), 2.63454 (m, 1H), 2.78(m, 1H), 2.93(s, (MH+) 3/2H), 2.94(s, 3/2H), 3.06(m,1H), 3.90(m, 2H), 4.60(m, 1H), 6.75(m, 1H), 6.96(dd, 1H, J=8.2, 1.9),7.08(m, 3H), 7.26(m, 3H), 7.42(d, 1H, J=8.0), 7.96 (m, 2H), 11.19(s, 1H)Intermed. 19 2.70(d, 1H, J=3.3), 3.50(dd, 1H, J=10.4, 8.5), 3.63(dd, 1H,J=10.4, 3.3), 4.92(m, 1H), 5.25 (s, 2H), 7.13(d, 1H, J=8.5), 7.30˜7.48(m, 5H), 7.53(dd, 1H, J=8.8, 2.5), 7.91(d, 1H, J=2.5) Intermed. 200.53˜0.62(m, 6H), 0.91(t, 9H, J=7.7), 3.31(m, 2H), 4.75(t, 1H, J=5.8),5.24(s, 2H), 7.13(d, 1H, J=8.8), 7.31˜7.52(m, 6H), 7.87(d, 1H, J=2.2)Intermed. 21 0.51˜0.60(m, 6H), 0.89(t, 9H, J=7.7), 2.78(dd, 1H, J=11.8,4.4), 2.89(dd, 1H, J=11.8, 7.7), 3.04(m, 2H), 4.12(m, 2H), 4.84 (dd, 1H,J=7.7, 4.4), 5.19(s, 2H), 6.80˜6.86(m, 2H), 7.05(d, 1H, J=8.5), 7.20(m,1H), 7.30˜7.52 (m, 7H), 7.86˜8.09(m, 5H) Intermed. 22 0.39˜0.57(m, 6H),0.77˜0.91(m, 745 9H), 3.40˜3.52(m, 1H), 3.49 (M+) (d, 2H, J=5.2),3.55˜3.68(m, 1H), 3.75(m, 1H), 3.88˜4.17(m, 2H), 5.10(s, 2H), 5.14(d,2H, J=10.2), 6.70˜6.83(m, 2H), 7.00 (dd, 1H, J=18.1, 8.8), 7.20(dd, 1H,J=8.0, 4.7), 7.27˜7.50(m, 12H), 7.80˜8.00(m, 4H) Intermed. 230.40˜0.58(m, 6H), 0.79˜0.92(m, 9H), 3.42˜3.50(m, 3H), 3.49 (d, 2H,J=7.7), 3.55˜3.66(m, 1H), 3.71(m, 1H), 3.86˜4.16(m, 2H), 5.03(d, 2H,J=2.5), 5.18(d, 2H, J=16.5), 6.71˜6.85(m, 2H), 7.16˜7.45(m, 16H),7.88(m, 1H), 7.96(d, 1H, J=7.1) Intermed. 24 0.40˜0.58(m, 6H),0.79˜0.92(m, 9H), 2.98(s, 3H), 3.42˜3.50 (m, 1H), 3.49(d, 2H, J=7.7),3.55˜3.66 (m, 1H), 3.17(m, 1H), 3.86˜4.16 (m, 2H), 5.03(d, 2H, J=2.5),5.18(d, 2H, J=16.5), 6.71˜6.85 (m, 2H), 7.16˜7.45(m, 16H), 7.88(m, 1H),7.96(d, 1H, J=7.1) Intermed. 25 2.86(d, 1H, J=3.6), 3.56(dd, 1H, J=10.7,8.5), 3.70(dd, 1H, J=10.7, 3.6), 5.06(dt, 1H, J=8.5, 3.6), 7.58(t, 1H,J=7.7), 7.75 (ddd, 1H, J=7.7, 1.1, 0.5), 8.20 (m, 1H), 8.30(dd, 1H,J=2.2, 1.6) Intermed. 28 (DMSO-d6): 0.50(m, 6H), 0.83(m, 9H), 2.72(m,2H), 2.96(s, 3H), 2.98(m, 2H), 4.08(m, 2H), 4.75 (m, 1H), 5.04(s, 2H),6.76(dd, 1H, J=8.8, 2.2), 6.96(d, 1H, J=1.9), 7.07˜7.13(m, 3H),7.24˜7.32 (m, 3H), 7.41(d, 1H, J=8.2), 7.96(m, 2H), 11.09(s, 1H)Intermed. 29 2.72(s, 3/2H), 2.73(s, 3/2H), 4.46(s, 2H), 7.70(dd, 1H,J=7.8, 7.8), 8.11(ddd, 1H, J=7.8, 1.8), 8.21(ddd, 1H, J=7.8, 1.8),8.45(dd, 1H, J=1.8, 1.8) Example 16 (DMSO-d6; HC1): 2.41(d, 3H), 3.16440 (m, 1H), 3.35(m, 1H), 3.49(m, (MH+) 2H), 4.42(m, 2H), 5.21(d, 1H,J=10.4), 6.48(bs, 1H), 6.84(d, 1H, J=8.2), 7.04(d, 1H, J=1.9), 7.11(t,1H, J=7.4), 7.29(m, 1H), 7.44(d, 2H, J=8.0 Hz), 7.50˜7.78 (m, 4H),7.88(s, 1H), 8.00 (d, 2H, J=8.0), 9.22(bs, 1H), 9.56(bs, 1H), 11.29(s,1H) Example 17 (DMSO-d6; HC1): 3.16(m, 1H), 3.28 390 (m, 1H), 3.50(m,2H), 4.41(m, (MH+) 2H), 5.08(m, 1H), 6.84(dd, 1H, J=8.2, 2.2), 7.03(d,1H, J=1.9), 7.11(t, 1H, J=7.4), 7.15˜7.55 (m, 7H), 7.74(m, 1H), 8.01 (m,2H), 9.09(bs, 1H), 9.38(bs, 1H), 11.25(s, 1H) Example 18 (DMSO-d6):2.77(m, 2H), 3.00(t, 408 2H, J=5.5), 4.12(t, 2H, J=5.5), (MH+) 4.68(m,1H), 5.17(br. s, 1H), 6.76(dd, 1H, J=8.5, 2.2), 6.96 (d, 1H, J=2.2),7.09(m, 2H), 7.28(m, 1H), 7.41(d, 1H, J=8.0), 7.53(dd, 1H, J=8.8, 2.2),7.87 (d, 1H, J=2.2), 7.97(m, 2H), 11.10(s, 1H) Example 19 (DMSO-d6;2HC1): 3.06(1H, m), 378 3.20(1H, m), 3.49(2H, m), 4.39 (MH+) (2H, m),4.95(1H, m), 6.19(1H, br. s), 6.84(1H, dd, J=8.5, 2.2), 7.00(1H, d,J=8.5), 7.03(1H, d, J=2.2), 7.12(2H, m), 7.30(2H, m), 8.01(2H, m),8.96(1H, br. s), 9.19(1H, br. s), 10.60(1H, br. s), 11.21(1H, s) Example20 (CD3 OD): 3.20˜3.29(2H, m), 3.53 505 (2H, t, J=4.7), 4.38(2H, t,J=4.7), (MH+) 4.90(1H, m), 5. 07(2H, s), 6.82(1H, d, J=8.2), 6.87(1H,dd, J=8.5, 2.2), 6.95(1H, dd, J=8.2, 1.9), 7.05(1H, d, J=1.1), 7.12(1H,dd, J=7.1, 1.1), 7.18˜7.46 (7H, m), 7.86(1H, d, J=1.9), 7.94(2H, d,J=8.5) Example 21 (DMSO-d6): 3.00(1H, m), 3.11 415 (1H, m), 3.39(2H, m),4.33(2H, (MH+) m), 4.80(1H, m), 5.86(1H, m), 6.25 (2H, s), 6.79(2H, s),6.83(1H, dd, J=8.5, 2.2), 7.02(1H, d, J=2.5), 7.12(1H, m) 7.30(1H, m),7.44(1H, d, J=8.2), 7.90˜8.02 (3H, m), 8.08(1H, s), 8.60(1H, br. s),10.02(1H, s), 11.17 (1H, s) Example 22 (CD3 OD): 2.92(1H, m), 3.04(1H,490 m), 3.63(2H, m), 4.18(2H, m), (MH+) 4.82(1H, m), 5.11(2H, s), 6.73(1H, dd, J=8.5, 2.2), 6.80(1H, d, J=8.2), 6.88(1H, m), 6.93(1H, d,J=1.9), 7.10(1H, dd, J=8.2), 7.24˜7.52(8H, m), 7.86˜7.95 (2H, m) Example23 (DMSO-d6; HC1): 2.82˜3.00(2H, 400 m), 3.44(2H, m), 4.34(2H, m), (MH+)4.46(1H, m), 6.83(2H, s), 6.86 (1H, m), 7.04(1H, d, J=2.2), 7.12 (1H,dd, J=8.0), 7.30(1H, dd, J=6.6, 7.7), 7.44(1H, d, J=8.5), 7.72(1H, m),8.02(2H, d, J=8.2), 8.91(1H, br. s), 9.28(1H, br. s), 9.76(1H, s),11.18(1H, s) Example 24 (DMSO-d6): 2.61(6H, s), 2.73 575 (2H, m),3.00(2H, m), 4.11(2H, (MH+) m), 4.61(1H, m), 5.16(2H, s), 5.38 (1H, m),6.76(1H, m), 6.96(1H, s), 7.02(1H, d, J=8.8), 7.10 (2H, m),7.24˜7.46(6H, m), 7.56 (2H, m), 7.97(2H, m), 11.09(1H, m) Example 25(DMSO-d6; HC1): 2.67(6H, s), 3.04 485 (1H, m), 3.18(1H, m), 3.45(2H,(MH+) m), 4.39(2H, m), 4.93(1H, m), 6.11(1H, br. s), 6.83(1H, dd, J=8.8,2.2), 6.91(1H, m), 7.03 (2H, m), 7.11(1H, m), 7.30(1H, m), 7.35(1H, d,J=2.2), 7.44(1H, d, J=7.7), 8.00(2H, m), 8.72 (1H, s), 8.99(1H, br. s),9.28 (1H, br.s), 10.07(1H, s), 11.25 (1H, s) Example 26 (DMSO-d6; 2HC1):2.81(s, 3H), 482 3.17(m, 1H), 3.27(m, 1H), 3.48 (MH+) (m, 2H), 4.38(m,2H), 5.00(m, 2H), 6.35(d, 1H, J=4.2), 6.84(dd, 1H, J=8.4, 2.7), 7.02(d,1H, J=2.1), 7.12(m, 1H), 7.27˜7.34 (m, 2H), 7.44(d, 1H, J=7.8),7.52˜7.59 (m, 2H), 8.01(m, 2H), 8.91(bs.2H), 10.21(bs.2H), 11.17 (s, 1H)Example 27 (DMSO-d6; 2HC1): 2.80(s, 3H), 392 3.17(m, 1H), 3.27(m, 1H),3.48 (MH+) (m, 2H), 4.38(m, 2H), 5.00(m, 2H), 6.35(d, 1H, J=4.2),6.84(dd, 1H, J=8.4, 2.7), 7.02(d, 1H, J=2.1), 7.12(m, 1H), 7.27˜7.34 (m,2H), 7.44(d, 1H, J=7.8), 7.52˜7.59 (m, 2H), 8.01(m, 2H), 8.91(bs, 2H),9.55(m, 1H), 10.21 (bs, 2H), 11.17(s, 1H) Intermed 30 2.79(dd, 1H,J=5.7, 2.7), 3.17 (dd, 1H, J=5.7, 4.2), 4.15(m, 1H), 7.01˜7.31(m, 4H)Example 28 (DMSO-d6; HC1): 3.19(m, 1H), 3.32 365 (m, 1H), 3.49(m, 2H),4.40(t, (MH+) 2H, J=5.1), 5.32(m, 1H), 6.34 (d, 1H, J=3.9), 6.84(dd, 1H,J=8.7, 2.4), 7.03(d, 1H, J=2.2), 7.12(m, 1H), 7.19˜7.34(m, 3H),7.36˜7.46(m, 2H), 7.59(dt, 2H, J=7.5, 1.8), 8.01(d, 2H, J=8.4) Intermed31 4.39(s, 2H), 5.15(s, 2H), 7.04 (m, 2H), 7.32˜7.46(m, 5H), 7.97 (m,2H) Intermed 32 (DMSO-d6): 2.72(m, 2H), 2.97(t, 2H, J=5.4), 4.10(t, 2H,J=5.4), 4.61(m, 1H), 5.26(bs, 1H), 6.76(dd, 1H, J=8.7, 2.1), 6.93˜6.98(m, 3H), 7.09(m, 1H), 7.2 4˜7.46(m, 9H), 7.95(t, 2H, J=8.4), 11.07(s,1H) Example 29 (DMSO-d6): 2.69(m, 2H), 2.96 363 (m, 2H), 4.10(m, 2H),4.58(m, 1H), (MH+) 5.12(bs, 1H), 6.67˜6.78(m, 3H), 6.96(d, 1H, J=1.2),7.06˜7.18 (m, 3H), 7.27(m, 1H), 7.41 (d, 1H, J=8.1), 7.95(m, 2H), 9.21(bs, 1H), 11.06(s, 1H) Intermed 33 (DMSO-d6): 2.62(dd, 1H, J=12.1, 8.5),2.83(m, 1H), 2.94(m, 2H), 4.07(m, 2H), 5.10(m, 1H), 5.23 (bs, 1H),6.76(dd, 1H, J=8.5, 2.2), 6.96(m, 2H), 7.03(d, 1H, J=8.2), 7.11(m, 1H),7.20(m, 1H), 7.25˜7.33(m, 2H), 7.34˜7.42 (m, 3H), 7.94˜7.97(m, 3M),7.97(m, 2H), 11.11(s, 1H) Example 30 (DMSO-d6; AcOH): 1.89(s, 3H), 3632.69(m, 1H,) 2.85(m, 1H), 2.99 (MH+) (m, 2H), 4.13(t, 2H, J=5.2), 4.91(m, 1H), 6.77(m, 3H), 6.96˜7.14 (m, 3H), 7.24˜7.33(m, 2H), 7.41(d, 1H,J=8.0), 7.97(m, 2H), 11.10(s, 1H) Example 31 (DMSO-d6): 2.6˜2.67(2H, m),2.97 347 (2H, bt), 4.11(2H, bt), 4.66 (MH+) (1H, bt), 5.33(1H, brs),6.76 (1H, dd, J=2.1, 8.4), 6.96(1H, d, J=2.1), 7.10(1H, dd, J=8.0),7.2˜7.38(6H, m), 7.41(1H, d, J=7.8), 7.95(1H, d, J=8.7), 7.97 (1H, d,J=7.5), 11.08(1H, s) Example 34 2.83(1H, dd, J=9, 12.3), 3.04(1H, 348dd, J=3.6, 12.3), 3.1˜3.16 (MH+) (2H, m), 4.19(2H, t, J=5.1), 4.78 (1H,dd, J=3.6, 9), 7.04(1H, dd, J=2.7, 9.0), 7.26˜7.48(9H, m), 7.55(1H, bd,J=8.4), 7.90 (1H, bd) Example 35 (DMSO-d6): 1.12(3H, d, J=6.3), 3612.77(2H, d, J=6.0), 3.07(1H, (MH+) q, J=6.3), 3.42(2H, t, J=6.0),4.49˜4.56(1H, m), 4.60˜4.66 (1H, m), 4.71(1H, t, J=5.8), 5.32 (1H, bd),6.73(1H, dd, J=2.2, 6.3), 6.94(1H, d, J=2.2), 7.10 (1H, dd),7.20˜7.39(6H, m), 7.42 (1H, d, J=8.0), 7.95(1H, d, J=8.8), 7.98(1H, d,J=9.0), 11.08 (1H, s) Intermed 34 (DMSO-d6): 1.85(s, 3H), 3.45(q, 2H,J=5.8), 4.06(t, 2H, J=5.8), 6.77(dd, 1H, J=8.5, 2.2), 6.97 (d, 1H,J=2.2), 7.10(m, 1H), 7.28(m, 1H), 7.41(d, 1H, J=8.0), 7.97(m, 2H),8.15(m, 1H), 11.11 (s, 1H) Intermed 35 1.8 5(s, 3H), 3.4 9(q, 2H,J=5.8), 4.23(t, 2H, J=5.8), 7.22(m, 2H), 7.41(m, 1H), 7.52(d, 1H,J=8.0), 8.10(m, 1H), 8.18(d, 1H, J=8.2), 8.81(s, 1H), 11.74(bs, 1H)Intermed 37 (DMSO-d6): 2.75(m, 2H), 3.02(t, 392 2H, J=5.5), 4.27(t, 2H,J=4.7), (MH+) 4.66(m, 1H), 5.31(d, 1H, J=4.1), 7.18˜7.26(m, 3H),7.27˜7.45 (m, 5H), 7.52(d, 1H, J=8.0), 8.19(d, 1H, J=8.0), 8.83(s, 1H),11.71(s, 1H) Example 36 (DMSO-d6): 2.73 m, 2H), 3.03(t, 378 2H, J=5.6),4.27(t, 2H, J=4.8), (MH+) 4.65(m, 1H), 5.31(d, 1H, J=4.1), 7.16˜7.25(m,3H), 7.27˜7.46 (m, 5H), 7.52(d, 1H, J=8.0), 8.18(d, 1H, J=8.0), 8.83(s,1H), 11.71(s, 1H) Intermed 38 (CDC13): 3.66(2H, m) 4.13(2H, 378 m),5.12(2H, s), 5.26(1H, br. s), (MH+) 7.01(1H, dd, J=8.8, 2.2), 7.23˜7.50(8H, m), 7.80(1H, m), 7.9 9˜8.60(2H, m) Intermed 39 (DMSO-d6): 2.93(2H,t, J=5.8), 244 4.04(2H, t, J=8.8, 2.5), 7.39˜7.49 (MH+) (2H, m),7.61(1H, d, J=2.5), 7.95(1H, dd, J=6.9, 1.9), 8.23 (2H, m) Example 37(CDC13): 2.82˜2.95(2H, m), 2.91 563 91(3H, s), 3.09(2H, m), 3.95(3H,(MH+) br. s), 4.18(2H, t, J=5.2), 4.75 (1H, m), 5.11(2H, s), 6.99(1H, d,J=8.5), 7.05(1H, dd, J=8.5, 2.2), 7.18(1H, dd, J=8.5, 2.2), 7.34(1H, d,J=2.5), 7.35˜7.46 (7H, m), 7.51(1H, d, J=1.9), 7.80(1H, m), 8.03(1H, d,J=8.8) 8.05(1H, dd, J=6.3, 1.4) Example 38 (DMSO-d6: HC1) 2.95(3H, s),3.08 473 (1H, m), 3.22(1H, m), 3.47(2H, m) (MH+) 4.44(2H, m), 4.92(1H,m), 6.12(1H, d, J=3.8), 6.94(1H, d, J=8.2), 7.09(1H, dd, J=8.2, 1.9),7.17(1H, dd, J=8.5, 2.2), 7.27(1H, d, J=1.9), 7.46(2H, m), 7.69(1H, d,J=2.2), 7.98(1H, m), 8.27(2H, m), 8.82(1H, br. s), 9.06(2H, br. s),10.06(1H, s) Intermed 40 (CDC13): 2.87(6H, s), 4.39(2H, 427 s), 5.20(2H,s), 6.89(1H, br. s), (M+) 7.03(1H, dd, J=8.5, 2 7), 7.35˜7.46 (5H, m),7.74(1H, dd, J=8.5, 2.2), 8.10(1H, d, J=2.2) Example 39 (DMSO-d6):2.61(6H, m), 2.67(2H, 592 d, J=6.6), 2.95(2H, m), 4.13 (MH+) (2H, m),4.56(1H, m), 5.16(2H, s), 5.28(1H, d, J=4.1), 7.01(1H, d, J=8.5),7.09(2H, dd, J=8.5, 2.2), 7.33(1H, d, J=7.4), 7.35˜7.40 (3H, m),7.44(2H, m), 7.55(2H, m), 7.60(1H, d, J=2.5), 7.96(1H, m), 8.23(2H, m)Example 40 (DMSO-d6: HC1): 2.67(6H, s), 2.99 502 (1H, m), 3.12(1H, m),3.12(1H, (MH+) m), 3.35(1H, s), 3.39(2H, m), 4.84(1H, m), 5.98(1H, br.s), 6.88(1H, d, J=8.2), 7.02(1H, dd, J=8.2, 1.9), 7.15(1H, dd, J=8.5,2.2), 7.34(1H, d, J=1.9), 7.46(2H, m), 7.67(1H, d, J=2.2), 7.98(1H, m),8.27(2H, m), 8.61 (2H, br. s), 10.01(1H, br. s) Example 41 (DMSO-d6:HC1): 3.00(3H, s), 3.08 457 (1H, m), 3.26(1H, m), 3.47(2H, (MH+) m),4.43(2H, m), 5.00(1H, m), 6.25(1H, m), 7.12˜7.20(3H, m), 7.30˜7.40(2H,m), 7.40˜7.51 (2H, m), 7.69(1H, d, J=2.2), 7.98(1H, m), 8.27(2H, m),9.05 (2H, br), 9.87(1H, br) Intermed 41 (CDC13): 2.71(1H, br. s), 2.79430 (6H, s), 3.51(1H, dd, J=10.2, 8.5), (MH+) 3.59(1H, dd, J=10.4, 3.6),4.48(1H, dd, J=8.5, 3.6), 5.12 (2H, s), 6.89(1H, br. s), 6.95 (1H, d,J=8.2), 7.09(1H, dd, J=8.5, 1.6), 7.33˜7.45(5H, m), 7.52 (1H, d, J=1.9)Intermed 42 (CDC13): 0.5 2˜0.63(6H, m), 0.87˜0.94 (9H, m), 2.77(6H, s),3.28˜3.33 (2H, m), 4.71(1H, m), 5.10(2H, s), 6.83(1H, br. s), 6.93 (1H,dd, J=8.5, 5.2), 7.05(1H, dd, J=8.5, 2.2), 7.37˜7.43 (5H, m), 7.50(1H,d, J=2.2) Intermed 43 (CDC13): 0.50˜0.59(6H, m), 0.89 690 (9H, m),2.76(6H, s), 2.71˜2.79 (MH+) (1H, m), 2.89(1H, dd, J=11.8, 8.2),3.06(2H, t, J=5.2), 4.15 (2H, t, J=5.2), 4.80(1H, dd, J=8.2, 4.1),5.09(2H, s), 6.90 (1H, d, J=8.2), 6.93(1H, dd, J=8.5, 2.2), 7.05(1H, dd,J=8.5, 2.2), 7.07(1H, d, J=2.2), 7.29 (1H, dd, J=7.4, 1.1), 7.34(1H, dd,J=5.2, 1.6), 7.36˜7.45(5H, m), 7.49˜7.54(2H, m), 7.80(1H, d, J=8.5),7.85(1H, m) Example 42 (CDC13): 2.78(6H, s), 2.72˜2.78 576 (1H, m),2.99(1H, dd, J=11.8, (MH+) 3.6), 3.11(2H, m), 4.17(2H, m), 4.68(1H, m),5.11(2H, s), 6.93 (1H, d, J=8.5), 6.94(1H, dd, J=8.5, 1.9),7.08˜7.12(2H, m), 7.30(1H, m), 7.34(1H, m), 7.36˜7.42 (5H, m), 7.52(2H,m), 7.81 (1H, d, J=8.5), 7.86(1H, m) Example 43 (DMSO-d6; HC1): 2.67(6H,s), 3.06 486 (1H, m), 3.19(1H, m), 3.48(2H, (MH+) m), 4.42(2H, m),4.88(1H, m), 6.11(1H, d, J=3.3), 6.88(1H, d, J=8.2), 7.03(1H, dd, J=8.2,1.9), 7.07(1H, dd, J=8.8, 2.2), 7.41˜7.50(4H, m), 7.66(1H, d, J=8.2),8.06(2H, m), 8.71(1H, s), 8.88(1H, br. s), 9.04(1H, br. s), 10.01(1H, s)Intermed 44 (CDC13): 0.50˜0.59(6H, m), 0.88 745 (9H, m), 2.17(3H, s),2.74(1H, (MH+) m), 2.76(6H, s), 2.87(1H, dd, J=11.8, 8.2), 3.02(2H, t,J=4.9), 3.77(2H, s), 4.08(2H, t, J=4.9), 4.80(1H, dd, J=8.0, 3.8),5.08(2H, s), 6.86(1H, dd, J=8.5, 2.2), 6.90(1H, d, J=8.5), 7.01(1H, d,J=1.9), 7.04(1H, dd, J=8.5, 1.9), 7.31(1H, dd, J=8.2, 1.6),7.35˜7.44(5H, m), 7.51˜7.58 (3H, m), 7.78(2H, m) Example 44 (CDC13):2.18(3H, s), 2.78(6H, 631 s), 2.72˜2.78(1H, m), 2.97(1H, (MH+) dd,J=11.8, 3.6), 3.07(2H, m), 3.77(2H, s), 4.10(2H, m), 4.68 (1H, m),5.10(2H, s), 6.89(1H, dd, J=8.5, 2.2), 6.91(1H, d, J=8.5), 7.02(1H, d,J=1.9), 7.04 (1H, dd, J=8.5, 1.9), 7.32(1H, dd, J=8.2, 1.7),7.35˜7.41(5H, m), 7.51˜7.57(3H, m), 7.79 (2H, m) Example 45 (DMSO-d6;HC1): 2.06(3H, s), 2.67 541 (6H, s), 2.86˜3.10(2H, m), (MH+) 3.26(2H,m), 3.86(2H, s), 4. 24 (2H, m), 4.76(1H, m) 5.80(1H, br. s), 6.85(1H, d,J=8.2), 6.99 (2H, m), 7.18(1H, d, J=2.1), 7.32 (1H, d, J=2.1), 7.48(1H,d, J=8.0), 7.70(2H, m), 7.88(1H, s), 10.01(1H, s) Example 46 (DMSO-d6):2.7˜2.86(2H, m), 2.95˜3.11 392 (2H, m), 4.07˜4.13(2H, (MH+) m), 4.84(1H,br. s), 5.69(1H, br. s), 6.76(1H, dd, J=8.5, 2.2), 6.96(1H, d, J=2.2),7.10(1H, dd, J=8.0, 8.0), 7.27(1H, dd, J=8.0, 8.0), 7.41(1H, d, J=8.0),7.62(1H, d, J=8.0, 8.0), 7.84 (1H, d, J=8.0), 7.95(1H, d, J=8.5),7.98(1H, d, J=8.0), 8.10 (1H, m), 8.25(1H, br. s), 11. 09 (1H, s)Example 47 (DMSO-d6): 2.68(2H, d, J=6.3), 362 2.96(2H, br. t, J=5.5),4.10(2H, (MH+) br. t, J=5.5), 4.50(1H, br. t), 4.96(2H, s), 5.14(1H, br.s), 6.42(1H, d, J=7.7), 6.48(1H, d, J=7.7), 6.59(1H, br. s), 6.76 (1H,dd, J=8.5, 2.2), 6.94(1H, dd, J=7.7, 7.7), 6.96(1H, d, J=2.2), 7.10(1H,dd, J=8.0, J=8.0), 7.27(1H, dd, J=8.0, 8.0), 7.41(1H, d, J=8.0),7.95(1H, d, J=8.5), 7.97(1H, d, J=8.0), 11.08(1H, s) Example 48(DMSO-d6): 2.89(6H, s), 2.9 4˜3.02 469 (2H, m), 3.29˜3.36(2H, m), (MH+)4.10(2H, br. t), 4. 63(1H, br. s), 5.41(1H, br. s), 6. 76(1H, d, J=8.8),6.95(1H, s), 7.0˜7.13 (3H, m), 7.2˜7.3(3H, m), 7.92˜8.0 (2H, m),11.09(1H, s) Example 49 (DMSO-d6): 2.06(3H, s), 2.68(2H, 602 d, J=6.0),2.89(3H, s), 2.93 (MH+) (2H, m), 3.83(2H, s), 4.06(2H, m), 4.58(1H, m),5.1 6(2H, s), 5.30(1H, br. s), 6.92(1H, dd, J=8.2, 1.9), 7.07(1H, d,J=8.5), 7.15(2H, m), 7.26˜7.50(5H, m), 7.53(2H, m), 7.67(2H, m), 7.85(1H, s), 9.95(1H, s) Example 50 (DMSO-d6; HC1): 2.06(3H, s), 2.95 512(3H, s), 3.05(1H, m), 3.20(1H, (MH+) m), 3.42(2H, m), 3.87(2H, s),4.34(2H, m), 4.89(1H, m), 6.08 (1H, s), 6.93(1H, d, J=8.5), 6.99(1H, m),7.08(1H, d, J=9.6), 7.20(1H, s), 7. 26(1H, s), 7.48 (1H, d, J=8.5),7.70(2H, m), 7.89(1H, s), 8.86(2H, br. s), 10.03 (2H, br) Example 51(DMSO-d6): 2.73(1H, dd, J=12.1, 560 9.6), 2.90(3H, s), 2.99(1H, (MH+)dd, J=12.1, 3.6), 3.07(2H, q, J=4.9), 3.49(1H, s), 3.77(2H, s), 4.11(2H,t, J=4.9), 4.67(1H, dd, J=9.6, 3.6), 5.10(2H, s), 6.69(1H, dd, J=8.2,2.2), 6.86 (2H, m), 6.97(1H, d, J=8.5), 7.04 (1H, m), 7.18(1H, dd,J=8.8, 1.9), 7.32˜7.50(7H, m), 7.53 (1H, m) Example 52 (DMSO-d6; 2HC1):2.95(3H, s), 470 3.07(1H, m), 3.17(1H, m), 3.43 (MH+) (2H, m), 3.94(2H,s), 4.37(2H, m), 4.91(1H, m), 6.09(1H, br. s), 6.94(1H, d, J=8.5),7.05(2H, m), 7.25(3H, m), 7.45(1H, s), 7.83(2H, m), 8.82(1H, s), 8.94(1H, br. s), 9.22(1H, br. s), 9.80 80(1H, br), 10.06(1H, s), 10.03 (2H,br. s) Intermed 45 (CDC13): 1.36(6H, d, J=9.6), 3.29 (1H, m), 4.40(2H,s), 5.20(2H, s), 6.79(1H, s), 7.05(1H, d, J=8.5), 7.35˜7.47(5H, m), 7.78(1H, dd, J=8.5, 2.2), 8.21(1H, d, J=2.2) Example 53 (DMSO-d6): 1.16(6H,d, J=6.9), 574 2.69(2H, d, J=6.3), 2.96(2H, (MH+) t, J=5.2), 3.12(1H,m), 4.10(2H, t, J=5.2), 4.58(1H, m), 5.14 (2H, s), 5.31(1H, m), 6.76(1H,dd, J=8.8, 1.7), 6.96(1H, d, J=1.9), 7.02˜7.15(3H, m), 7.25˜7.44 (6H,m), 7.54(2H, m), 7.97 (2H, m), 11.10(1H, s) Example 54 (DMSO-d6; HC1):1.27(6H, d, J=6.9), 484 2.95˜3.28(3H, m), 3.47(2H, (MH+) m), 4.39(2H,m), 4.91(1H, m), 6.11(1H, br. s), 6.84(1H, dd, J=8.5, 2.2), 6.92(1H, m),7.05 (2H, m), 7.12(1H, t, J=7.4), 7.30 (2H, m), 7.44(1H, d, J=8.2),8.00(2H, m), 8.73(1H, s), 8.94 (1H, m), 9.18(1H, br. s), 10.07 (1H, s),11.23(1H, s) Intermed 46 (CDC13): 0.52˜0.62(6H, m), 0.87˜0.94 (9H, m),3.03(3H, s), 3.3˜3.34 (2H, m), 4.74(1H, m), 6.54 (1H, br. s),7.08˜7.2(2H, m), 7.57(1H, dd, J=7.6, 2.2) Intermed 47 (CDC13):0.51˜0.6(6H, m), 0.85˜0.92 (9H, m), 2.78(1H, dd, J=11.8, 4.0), 2.87(1H,dd, J=11.8, 8.0), 3.00(3H, s), 3.06(2H, t, J=5.2), 4.16(2H, t, J=5.2),4.84(1H, dd, J=8.0, 4.0), 6.93 (1H, dd, J=8.5, 2.2), 7.08(1H, d, J=2.2),7.10(1H, m), 7.15˜7.21 (1H, m), 7.31(1H, m), 7.38(1H, m), 7.52(1H, d,J=8.2), 7.59 (1H, dd, J=8.0, 2.2), 7.81(1H, d, J=8.5), 7.86(1H, m)Example 55 (DMSO-d6; HC1): 3.05(3H, s), 3.12 459 (1H, m), 3.29(1H, m),3.48(2H, (MH+) m), 4.43(2H, m), 5.01(1H, m), 6.31(1H, d, J=4.4),7.08(1H, dd, J=8.5, 2.2), 7.29(1H, m), 7.32˜7.50(6H, m), 7.66(1H, d,J=8.0), 8.07(2H, m), 8.96(2H, m), 9.71(1H, s) Intermed 48 (CDC13):0.55˜0.61(6H, m), 0.85˜0.92 (9H, m), 2.77(1H, dd, J=11.8, 4.1), 2.88(1H,dd, J=11.8, 7.8), 2.99(3H, s), 3.06(2H, t, J=5.2), 4.16(2H, t, J=5.2),4.83(1H, dd, J=7.8, 4.1), 7.04 (1H, dd, J=8.8, 2.5), 7.10(1H, m),7.15˜7.21(1H, m), 7.32(1H, d, J=2.2), 7.35˜7.46(2H, m), 7.58(1H, dd,J=7.7, 2.1), 7.80 (1H, m), 8.03(1H, d, J=8.8), 8.04 (1H, m) Example 56(DMSO-d6; HC1): 3.05(3H, s), 3.11 475 (1H, m), 3.32(1H, m), 3.49(2H,(MH+) m), 4.42(2H, m), 4.98(1H, m), 6.31(1H, d, J=3.3), 7.17(1H, dd,J=8.8, 2.5), 7.27˜7.37(2H, m), 7.43˜7.52(3H, m), 7.69(1H, d, J=2.5),7.98(1H, m), 8.28 (2H, m), 8.95(2H, br. s), 9.71 (1H, s) Intermed 49(CDC13): 0.54˜0.63(6H, m), 0.87˜0.95 (9H, m), 3.02(3H, s), 3.28˜3.34(2H, m), 4.74(1H, m), 6.81(1H, br. s), 7.16(1H, dd, J=8.2, 2.2),7.40(1H, d, J=8.2), 7.65(1H, d, J=2.2) Intermed 50 (CDC13):0.52˜0.62(6H, m), 0.86˜0.93 (9H, m), 2.80(1H, dd, J=12.0, 4.2), 2.88(1H,dd, J=12.0, 8.0), 2.98(3H, s), 3.08(2H, t, J=5.2), 4.15(2H, t, J=5.2),4.85(1H, dd, J=8.0, 4.2), 6.92 (1H, dd, J=8.5, 2.2), 7.08(1H, d, J=2.2),7.17(1H, dd, J=8.2, 1.9), 7.28˜7.41(3H, m), 7.5˜7.56 (1H, m), 7.67(1H,d, J=2.2), 7.81(1H, d, J=8.2), 7.86(1H, m) Example 57 (DMSO-d6; HC1):3.06(3H, s), 3.12 475 (1H, m), 3.29(1H, m), 3.48(2H, m), (MH+) 4.42(2H,m), 5.01(1H, m), 6.34(1H, m), 7.07(1H, dd, J=8.8, 2.2), 7.31(1H, dd,J=8.2, 2.2), 7.34˜7.41(2H, m), 7.45(1H, m), 7.52(1H, d, J=1.9), 7.57(1H, d, J=8.2), 7.66(1H, m), 8.06 (2H, m), 9.02(2H, br. s) Intermed 51(CDC13): 0.52˜0.62(6H, m), 0.86˜0.92 (9H, m), 2.79(1H, dd, J=12.1, 4.1),2.87(1H, dd, J=12.1, 7.7), 2.97(3H, s), 3.05(2H, br. t), 4.15(2H, br.t), 4.84(1H, dd, J=7.7, 4.1), 7.03(1H, dd, J=8.7, 2.5), 7.16(1H, dd,J=8.7, 2.2), 7.31(1H, d, J=2.5), 7.35˜7.46(3H, m), 7.66(1H, d, J=2.2),7.80(1H, m), 8.02(1H, d, J=8.4), 8.04(1H, m) Example (DMSO-d6; HC1):3.06(3H, s), 3.08˜3.15 491 58 (1H, m), 3.27˜3.35(1H, (MH+) m),3.44˜3.53(2H, m), 4.40˜4.48 (2H, m), 5.0˜5.09(1H, m), 6.37(1H, br. s),7.17(1H, dd, J=8.6, 2.2), 7.31(1H, dd, J=8.2, J=1.9), 7.46˜7.57(2H, m),7.53 (1H, d, J=1.9), 7.56(1H, d, J=8.2), 7.68(1H, d, J=2.5), 7.95˜7.99(1H, m), 8.23˜8.3(2H, m), 9.02(1H, br. s), 9.18(1H, br.s), 9.55(1H, s)Intermed 52 (CDC13): 2.60(3H, s), 2.90(6H, s), 6.53(1H, br. s), 7.19(1H,dd, J=8.5, 7.7), 7.73(1H, m), 8.14 (1H, dd, 7.7, 2.2) Intermed 53(CDC13): 2.90(6H, s), 4.41(2H, s), 6.69(1H, br. s), 7.23(1H, dd, J=9.9,8.8), 7.77(1H, ddd, J=7.0, 4.9, 2.2), 8.17(1H, dd, 7.4, 2.2) Example 59(DMSO-d6; HC1): 2.71(6H, s), 3.0˜3.14 487 (1H, br. s), 3.22˜3.34 (MH+)(1H, br. s), 3.43˜3.53(2H, m), 4.33˜4.46(2H, m), 5.02(1H, m), 6.34(1H,br. s), 6.83(1H, dd, J=8.5, 2.2), 7.03(1H, d, J=2.2), 7.12(1H, dd,J=7.7, 7.7), 7.2˜7.38 (3H, m), 7.44(1H, d, J=8.0), 7.52(1H, dd, J=7.7,2.0), 8.00(2H, d, J=8.5), 8.94˜9.10 (1H, br. s), 9.14˜9.30(1H, br. s),9.71(1H, s), 11.22(1H, s) Intermed 54 (CDC13): 2.60(3H, s), 2.89(6H, s),6.85(1H, br. s), 7.48(1H, d, J=8.2), 7.65(1H, dd, J=8.2, 1.9), 8.17(1H,d, 1.9) Intermed 55 (CDC13): 2.90(6H, s), 4.41(2H, s), 6.90(1H, br. s),7.52(1H, d, J=8.5), 7.68(1H, dd, J=8.5, 1.9), 8.20(1H, d, J=1.9)Intermed 56 (CDC13): 2.79(3H, s), 9.08(2H, d, J=2.2), 9.25(1H, dd,J=2.2) Intermed 57 (CDC13): 2.63(3H, s), 4.19(2H, br. s), 7.53(1H, dd,J=2.2), 7.67 (1H, dd, J=2.2), 8.10(1H, dd, J=2.2) Intermed 58 (CDC13):2.68(3H, s), 6.34(1H, br. s), 7.79(1H, dd, J=2.5), 7.92 (1H, dd, J=2.2),8.34(1H, dd, J=1.9) Intermed 59 (CDC13): 2.66(3H, s), 5.20(2H, s),7.30˜7.48(5H, m), 7.88(1H, dd, J=2.5), 8.01(1H, dd, J=2.5, 1.9),8.36(1H, dd, J=1.9) Intermed 60 (CDC13): 2.53(3H, s), 3.80(2H, br. s),5.07(2H, s), 6.50(1H, dd, J=1.9), 6.89(1H, dd, J=1.9), 6.98(1H dd,J=2.2), 7.30˜7.48 (5H, m) Examp1e 60 (DMSO-d6; HC1): 2.73(6H, s), 3.0˜503 3.15(1H, m), 3.24˜3.36(1H, (MH+) m), 3.4˜3.54(2H, m), 4.35˜4.46 (2H,m), 5.05(1H, m), 6.38(1H, br. s), 6.84(1H, dd, J=8.5, 2.2), 7.03(1H, d,J=2.2), 7.12(1H, dd, J=8.0, 8.0); 7.23˜7.34 (2H, m), 7.44(1H, d, J=8.0),7.52 (1H, d, J=8.2), 7.61(1H, d, J=1.9), 8.01(2H, d, J=8.5), 8.94˜9.08(1H, br. s), 9.15˜9.28(1H, br. s), 9.46(1H, s), 11.22(1H, s) Intermed 61(CDC13): 2.58(3H, s), 3.00(3H, s), 5.12(2H, s), 6.88(1H, bs), 7.15(1H,d, J=2.2), 7.27˜7.4 7(7H, m) Intermed 62 (CDC13): 3.02(3H, s), 4.40(2H,s), 5.13(2H, s), 6.95(1H, br. s), 7.15˜7.18(1H, m), 7.31˜7.50 (7H, m)Examp1e 61 (CDC13): 2.74(2H, m), 2.86(3H, 546 s), 2.96(2H, m), 4.00(2H,m), (MH+) 4.68(1H, d, J=5.5), 4.94(2H, s), 6.74(4H, m), 6.84(1H, s),7.18 (1H, m), 7.27˜7.39(7H, m), 7.85 (1H, d, J=8.5), 7.92(1H, d, J=7.4),8.26(1H, br. s) Examp1e 62 (DMSO-d6): 2.98(3H, s), 3.23(2H, 456 m),3.47(2H, m), 4.39(2H, t, (MH+) J=4.7), 4.91(1H, d, J=10.4), 6.19(1H, d,J=3.6), 6.57(1H, s), 6.64(1H, dd, J=1.9), 6.73(1H, s), 6.84(1H, dd,J=8.8, 2.5), 7.03(1H, d, J=2.2), 7.12(1H, dd, J=7.4), 7.30(1H, dd,J=7.1), 7.44(1H, d, J=8.0) Intermed 63 (CDC13): 2.73(3H, s), 7.05(1H,dd, J=8.0), 8.06(1H, d, J=8.0), 8.20(1H, d, J=8.2) Intermed 64 (CDC13):2.75(3H, s), 7.10(1H, d, J=9.3), 8.36(1H, dd, J=9.3, 2.8), 8.72(1H, d,J=2.8) Intermed 65 (CDC13): 2.66(3H, s), 3.95(3H, s), 7.30(1H, d,J=8.0), 7.82(1H, dd, J=8.0, 1.9), 7.93(1H, dd, J=8.0, 1.9) Intermed 66(CDC13): 2.62(3H, s), 3.78(3H, s), 3.92(2H, br. s), 6.89(1H, dd, J=7.1,2.5), 6.97(1H, d, J=6.9), 6.98(1H, d, J=2.5) Intermed 67 (CDC13):2.63(3H, s), 3.08(3H, s), 3.82(3H, s), 7.05(1H, br. s), 7.19(1H, dd,J=8.0), 7.38 (1H, dd, J=8.0, 1.7), 7.71(1H, dd, J=8.2, 1.7) Intermed 68(CDC13): 2.61(3H, s), 3.01(3H, s), 3.83(3H, s), 4.82(2H, s), 7.06(1H,dd, J=8.0, 7.8), 7.19˜7.30 (6H, m), 7.52(1H, dd, J=8.0, 1.9) Intermed 69(CDC13): 3.01(3H, s), 3.87(3H, s), 4.49(2H, s), 4.83(2H, s), 7.11(1H,dd, J=8.0, 7.8), 7.19˜7.31 (6H, m), 7.57(1H, dd, J=8.0, 1.9) Intermed 70(CDC13): 2.74(1H, d, J=8.8), 2.93 (3H, s), 2.98˜3.14(3H, m), 3.80(3H,s), 4.15(2H, m), 4.81 (2H, m), 5.04(1H, d, J=8.8), 6.84 (1H, d, J=8.5),6.87(1H, br. s), 7.01(1H, d, J=8.0), 7.06(1H, dd, J=7.4), 7.1 7˜7.40(8H, m), 7.50(1H, d, J=7.4), 7.91(1H, d, J=8.2), 7.96(1H, d, J=7.7),8.12(1H, br. s) Intermed 71 (DMSO-d6): 2.9˜3.1(2H, m), 3.12 (3H, s),3.15˜3.30(2H, m), 4.34˜4.44 (2H, m), 4.76(2H, m), 5.30(1H, d, J=9.6),6.2˜6.4(1H, br. s), 6.78˜6.98(2H, m), 7.02˜7.38 (10H, m), 7.44(2H, d,J=8.0), 7.95(1H, dd, J=7.7, 8.2), 8.01(2H, d, J=8.2) Examp1e 63 (CD3OD): 2.85(3H, s), 2.96˜3.20 456 (4H, m), 4.21(2H, t, J=5.0), (MH+)4.98(1H, m), 6.77(1H, dd, J=7.7), 6.81(1H, dd, J=8.9, 2.2), 6.99(1H, d,J=2.2), 7.07˜7.14 (2H, m), 7.23˜7.30(2H, m), 7.38 (1H, d, J=8.2),7.91(2H, dd, J=8.2) Intermed 72 (CDC13): 2.65(3H, s), 4.05(3H, s),7.08(1H, d, J=9.1), 8.36(1H, dd, J=9.1, 3.0), 8.63(1H, d, J=2.8)Intermed 73 (CDC13): 2.60(3H, s), 3.50(2H, br. s), 3.84(3H, s), 6.82(2H,m), 7.08(1H, m) Intermed 74 (CDC13): 2.63(3H, s), 2.97(3H, s), 3.93(3H,s), 6.39(1H, br. s), 7.01(1H, d, J=9.1), 7.51˜7.57 (2H, m) Intermed 75(CDC13): 2.59(3H, s), 2.95(3H, s), 3.88(3H, s), 4.81(2H, s), 6.87(1H, d,J=9.1), 7.22˜7.28 (5H, m), 7.30(1H, dd, J=8.8, 2.8), 7.71(1H, d, J=3.0)Intermed 76 (CDC13): 2.96(3H, s), 3.92(3H, s), 4.56(2H, s), 4.81(2H, s),6.90(1H, d, J=8.8), 7.22˜7.28 (5H, m), 7.37(1H, dd, J=9.1, 3.0),7.77(1H, d, J=2.8) Intermed 77 (CDC13): 2.6˜3.0(2H, m), 2.94 (3H, s),3.04˜3.08(2H, m), 3.70 (3H, s), 4.14(2H, t, J=5.8), 4.79 (2H, d, J=9.9),4.99(1H, m), 6.60(1H, d), 6.80˜6.86(2H, m), 7.03(1H, dd, J=8.5, 3.0),7.18˜7.42 (8H, m), 7.88˜8.00(3H, m), 8.07(1H, m) lntermed 78 (CD3 OD):3.01(3H, s), 3.31(2H, m), 3.54(2H, m), 4.38(2H, t, J=5.0), 4.78˜4.82(2H,m), 5.27 (1H, m), 6.72˜6.95(2H, m), 7.05 (1H, d, J=1.9), 7.08˜7.48(11H,m), 7.95(2H, d, J=7.1) Example 64 (CD3 OD): 2.88(3H, s), 3.19(2H, 456m), 3.62(2H, m), 4.22(2H, m), (MH+) 5.24(1H, m), 6.72˜7.48(9H, m),7.85˜7.95(2H, m) Intermed 79 (CDC13): 2.61(3H, s), 5.45(2H, s), 7.22(1H,d, J=8.8), 7.34˜7.55 (5H, m), 8.26(1H, dd, J=8.8, 2.2), 8.55(1H, d,J=2.5) Intermed. 79′ (CDC13): 2.57(3H, d, J=5.2), 2.61 (3H, s), 4.70(1H,q, J=5.5), 5.32(2H, s), 7.17(1H, d, J=8.8), 7.24˜7.51(5H, m), 8.18(1H,dd, J=8.8, 2.2), 8.50(1H, d, J=2.2) Intermed 80 (CDC13): 2.58(3H, s),4.43(2H, s), 4.74(1H, s), 5.34(2H, s), 7.20(1H, d, J=8.8), 7.36˜7.51(5H, m), 8.20(1H, dd, J=8.8, 2.2), 8.52(1H, d, J=2.2) Example 65(DMSO-d6): 2.42(3H, d, J=5.0), 546 2.71(2H, d, J=6.0), 2.95(2H, (MH+) t,J=5.2), 4.08(2H, t, J=5.5), 4.64(1H, m), 5.33(2H, s), 5.42 (1H, d,J=4.1), 6.75(1H, dd, J=8.5, 2.2), 6.93˜7.00(2H, m), 7.10 (1H, dd, J=7.7,7.4), 7.15(1H, d, J=8.5), 7.24˜7.54(8H, m), 7.76(1H, d, J=2.2),7.92˜8.00 (2H, m), 11.08(1H, s) Example 66 (DMSO-d6; HC1): 2.41(3H, d,J=5.0), 456 3.0 3˜3.35(2H, m), 3.47(2H, (MH+) m), 4.39(2H, m), 5.00(1H,d, J=10.4), 6.21(1H, br. s), 6.84 (1H, dd, J=8.5, 2.2), 6.88(1H, d,J=5.2), 7.03(1H, d, J=2.2), 7.08(1H, d, J=8.2), 7.13(1H, d, J=8.0),7.30(1H, ddd, J=8.2, 1.1), 7.44(1H, d, J=8.0), 7.47 (1H, dd, J=8.8,2.2), 7.71(1H, d, J=2.2), 8.01(2H, d, J=8.5), 8.90˜9.05(1H, br. s),9.10˜9.25 (1H, br. s), 10.89(1H, s), 11.21 (1H, s) Intermed 82 (CDC13):2.58(3H, s), 3.94(3H, s), 5.28(2H, s), 7.07(1H, d, J=8.8), 7.30˜7.52(5H,m), 8.08 (1H, dd, J=8.8, 2.5), 8.44(1H, d, J=2.2) Intermed 83 (CDC13):3.94(3H, s), 4.42(2H, s), 5.29(2H, s), 7.10(1H, d, J=8.8), 7.34˜7.50(5H,m), 8.11 (1H, dd, J=8.8, 2.5), 8.47(1H, d, J=2.2) Intermed 84 (CDC13):2.77(1H, d, J=12.3), 511 2.99(1H, d, J=12.3), 3.08(2H, (MH+) m),3.89(3H, s), 4.13(2H, t, J=5.1), 4.72(1H, d, J=8.7), 5.14 (2H, s),6.83(2H, m), 6.95(1H, d, J=8.5), 7.20(1H, m), 7.30˜7.48 (8H, m),7.84(1H, d, J=2.2), 7.91(1H, d, J=9.3), 7.96(1H, d, J=7.7), 8.12(1H, br.s) Intermed 85 (CDC13): 2.81(1H, d, J=11.8), 411 2.99(1H, d, J=12.1),3.10(2H, (MH+) m), 4.17(2H, t, J=5.0), 4.71(1H, m), 4.75(2H, s),5.12(2H, s), 6.85(1H, d, J=8.5), 6.88(1H, s), 6.94(1H, d, J=8.2),7.20˜7.42 (9H, m), 7.93(1H, d, J=8.8), 7.97(1H, d, J=7.7), 8.20(1H, br.s) Example 67 (DMSO-d6; HC1): 3.71(1H, br. s), 393 3.19(1H, br. s),3.48(2H, br. (MH+) s), 4.38(2H, m), 4.49(2H, s), 4.90(1H, d, J=10.2),5.04(1H, br. s), 6.03(1H, d, J=3.3), 6.78 (1H, d, J=8.2), 6.84(1H, dd,J=8.2, 2.2), 7.02(1H, d, J=2.2), 7.07(1H, d, J=7.4), 7.12(1H, dd, J=7.4,7.4), 7.30(1H, dd, J=8.0, 8.0), 7.36(1H, s), 7.44(1H, d, J=7.7),8.01(2H, d, J=8.5) Intermed 86 (CDC13): 2.73(1H, br. s), 3.03 (3H, s),3.53(1H, dd, J=10.44, 8.8), 3.66(1H, dd, J=10.44, 3.3), 4.94(1H, dd,J=8.8, 3.6), 6.57 (1H, br. s), 7.17˜7.24(2H, m), 7.26(1H, m), 7.38(1H,m) Intermed 87 (CDC13): 0.4 7˜0.68(6H, m), 0.91 (9H, t, J=7.7), 3.01(3H,s), 3.33(2H, d, J=5.8), 4.75(1H, t, J=5.8), 6.49(1H, br. s), 7.13˜7.19(2H, m), 7.22(1H, m), 7.3 3(1H, t, J=7.7) Intermed 88 (CDC13):1.58˜1.73(2H, m), 2.00 (3H, s), 2.20˜2.32(2H, m), 2.35˜2.55 (4H, m),4.25(1H, m), 5.48(1H, br, s) Intermed 89 (DMSO-d6): 1.75(1H, m), 1.82(3H, s), 1.94(1H, m), 2.42(1H, dd, J=14.6, 8.5), 3.73(3H, s), 4.01(1H,m), 6.57(1H, dd, J=8.2, 2.2), 6.75(1H, d, J=2.2), 7.18 (1H, d, J=8.5),7.93(1H, d, J=8.0), 10.50(1H, s) Intermed 90 (DMSO-d6): 2.05(3H, s),3.83 (3H, s), 6.74(1H, dd, J=8.5, 2.2), 6.93(1H, d, J=2.2), 7.30˜7.40(2H, m), 7.86(1H, d, J=8.8), 8.21(1H, d, J=1.9), 9.85(1H, s), 11.00(1H,s) Intermed 91 (DMSO-d6): 2.05(3H, s), 6.60 (1H, dd, J=8.5, 1.9),6.77(1H, d, J=1.6), 7.26(1H, d, J=8.5), 7.34(1H, dd, J=8.5, 1.6), 7.74(1H, d, J=8.5), 8.15(1H, s), 9.38 (1H, s), 9.82(1H, s), 10.83 (1H, s)Intermed 92 (DMSO-d6): 2.06(3H, s), 3.43 (2H, m), 4.07(2H, m), 5.05(2H,s), 6.74(1H, dd, J=8.5, 1.9), 6.94 (1H, s), 7.25˜7.50(7H, m), 7.54(1H,t, J=5.5), 7.86(1H, d, J=8.5), 8.22(1H, s), 9.86(1H, s), 11.02(1H, s)Intermed 93 (DMSO-d6): 1.8˜2.1(2H, br. s), 2.05(3H, s), 2.93(2H, t,J=5.8), 4.00(2H, t, J=5.8), 6.74(1H, dd, J=8.5, 2.2), 6.93(1H, d,J=2.2), 7.30˜7.40(2H, m), 7.86 (1H, d, J=8.8), 8.21(1H, d, J=1.9),9.85(1H, s), 11.00(1H, s) Example 68 (DMSO-d6: HC1): 2.06(3H, s), 3.00497 (3H, s), 3.17(1H, m), 3.27(1H, m), (M+) 3.48(2H, m), 4.37(2H, m),4.97(1H, m), 6.26(1H, m), 6.82 (1H, m), 6.99(1H, m), 7.15(2H, m),7.30˜7.40(4H, m), 7.92(1H, d, J=8.8), 8.27(1H, s), 8.91 (2H, m),9.86(1H, s), 9.89(1H, s), 11.09(1H, s) Intermed 95 (CDC13):0.49˜0.58(6H, m), 0.88 689 (9H, m), 2.75(6H, s), 2.72˜2.79 (MH+) (1H,m), 2.81˜2.94(1H, m), 3.01(2H, m), 4.12(2H, m), 4.80 (1H, dd, J=7.7,4.1), 5.07(2H, s), 6.82(1H, dd, J=8.5, 2.2), 6.93 (1H, dd, J=8.5, 2.2),7.05 (1H, dd, J=8.5, 2.2), 7.07(1H, d, J=2.2), 7.29(1H, dd, J=7.4, 1.1),7.34(1H, dd, J=5.2, 1.6), 7.36˜7.45(5H, m), 7.49˜7.54 (2H, m), 7.80(1H,d, J=8.5), 7.85 (1H, m) Intermed. 102 (CDC13): 0.51˜0.60(6H, m), 0.88(9H, m), 2.78(1H, dd, J=11.8, 4.1), 2.89(1H, dd, J=11.8, 7.7), 2.99(3H,s), 3.05(2H, t, J=4.9), 4.15(2H, t, J=4.9), 4.83 (1H, dd, J=7.7, 4.1),6.82(1H, dd, J=8.5, 2.2), 6.91(1H, d, J=2.2), 7.05˜7.28(3H, m),7.31˜7.42 (2H, m), 7.59(1H, dd, J=8.0, 1.9), 7.90˜8.00(2H, m), 8.12 (1H,br. s) Intermed. 108 (CDC13): 0.52˜0.61(6H, m), 0.89 (9H, m), 2.79(1H,dd, J=12.1, 4.4), 2.89(1H, dd, J=12.1, 7.7), 2.96(3H, s), 3.04(2H, m),4.15 (2H, m), 4.84(1H, m), 6.82 (1H, dd, J=8.5, 2.2), 6.92(1H, d,J=1.9), 7.17(1H, dd, J=8.8, 1.9), 7.21(1H, dd, J=8.2, 1.4),7.30˜7.42(3H, m), 7.67(1H, d, J=2.2), 7.90˜7.99(2H, m), 8.14 (1H, br. s)Intermed. 112 (CDC13): 2.49(3H, d, J=5.2), 3.28 (1H, d, J=3.0), 3.47(1H,dd, J=10.7, 8.0), 3.56(1H, dd, J=10.7, 4.1), 4.83(1H, q, J=5.5),4.88(1H, m), 5.22(2H, s), 7.09, (1H, d, J=8.8), 7.30˜7.48(5H, m),7.55(1H, dd, J=8.8, 2.5), 7.88(1H, d, J=2.2) Intermed. 113 (CDC13):0.47˜0.66(6H, m), 0.85˜0.95 (9H, m), 2.52(3H, d, J=5.5), 3.28˜3.35(2H,m), 4.66 (1H, m), 4.77(1H, m), 5.23(2H, s), 7.09(1H, d, J=8.5),7.34˜7.52 (5H, m), 7.55(1H, dd, J=8.5, 2.5), 7.91(1H, d, J=2.2)Intermed. 114 (CDC13): 0.48˜0.58(6H, m), 0.87 (9H, m), 2.50(3H, d,J=5.5), 2.80(1H, dd, J=11.8, 4.4), 2.91 (1H, dd, J=11.8, 7.4), 4.07(2H,m), 4.69(1H, q, J=5.5), 4.86 (1H, dd, J=7.4, 4.4), 5.15(2H, s), 6.77(1H,d, J=1.9), 6.82(1H, dd, J=6.3, 2.2), 7.01(1H, d, J=8.5), 7.20(1H, m),7.30˜7.48 (7H, m), 7.52(1H, dd, J=8.5, 2.2), 7.89˜8.00(2H, m), 8.19(1H,S), Intermed. 116 (CDC13): 2.34(3H, s), 2.64(3H, S), 8.21(1H, dd, J=9.1,2.2), 8.81(1H, d, J=2.2), 8.95(1H, d, J=9.1) Intermed. 117 (CDC13):2.25(3H, s), 2.56(3H, S), 7.44(2H, m), 7.50(1H, m) Intermed. 118(CDC13): 2.26(3H, s), 2.60(3H, S), 3.05(3H, s), 6.79(1H, s), 7.90(2H,m), 8.24(1H, dd, J=8.1, 2.5), 8.55(1H, br. s) Intermed. 119 (CDC13):2.27(3H, s), 3.08(3H, s), 4.41(2H, s), 6.73(1H, br. s), 7.87˜8.09(2H,m), 8.31(1H, dd, J=8.8), 8.58(1H, d, J=10.2) Intermed. 120 (DMSO-d6;HC1): 2.10(3H, s), 2.94 497 (3H, s), 3.15(2H, d, J=8.2) (MH+) 3.48(2H,m), 4.39(2H, m), 5.01 (1H, m), 6.26(1H, m), 6.84(1H, d, J=8.5), 7.03(1H,s), 7.12(1H, dd, J=7.1, 6.9), 7.24˜7.33 (2H, m), 7.44(2H, d, J=8.5),7.56 (1H, m), 8.01(2H, d, J=6.9), 8.8˜9.1(2H, m), 9.62(1H, m), 11.18(1H, s) Example 82 (DMSO-d6; 2HC1): 3.02(3H, s), 455 3.2˜3.5(4H, m),4.26(2H, m), 4.84 (MH+) (1H, d, J=9.3), 6.8˜7.5(8H, m), 7.64(1H, s),7.87(1H, d, J=7.7), 8.01(1H, d, J=8.2), 9.0˜9.6 (3H, br. s), 11.3(1H, s)Intermed. 121 (CDC13): 2.61(3H, s), 2.62(3H, s), 4.18(2H, s), 5.27(2H,s), 7.15(3H, m), 7.35˜7.44(3H, m), 7.47(2H, d, J=8.0), 8.16(1H, dd,J=8.8, 2.2), 8.57(1H, d, J=2.2) Intermed. 122 (CDC13): 2.62(3H, s),4.19(2H, s), 4.43(2H, s), 5.28(2H, s), 7.12˜7.20(2H, m), 7.18(1H, d,J=8.52), 7.24˜7.50(8H, m), 8.20 (1H, dd, J=8.5, 2.2), 8.59(1H, d, J=2.2)Intermed. 123 (CDC13): 2.59(3H, s), 2.72˜2.82 636 (1H, m), 3.00˜3.08(1H,m), 3.10 (MH+) (2H, m), 4.13˜4.20(4H, m), 4.72˜4.77(1H, m), 5.16(2H, s),6.84(1H, dd, J=8.2, 2.2), 6.91 (1H, d, J=2.2), 7.05(1H, d, J=8.5),7.13˜7.49(13H, m), 7.57 (1H, d, J=8.2), 7.93(1H, d, J=8.5), 7.97(1H, d,J=7.7), 8.01 (1H, d, J=1.7) Example 83 (DMSO-d6; HC1): 2.64(3H, s), 3.14546 (2H, m), 3.48(2H, m), 4.31(2H, (MH+) s), 4.39(2H, m), 5.00(1H, m),6.23(1H, br. s), 6.83(1H, dd, J=8.8, 2.2), 7.02(1H, d, J=1.9),7.08˜7.15(3H, m), 7.26˜7.40(6H, m), 7.43(1H, d, J=8.5), 7.51(1H, dd,J=8.8, 1.9), 7.80 (1H, d, J=1.9), 7.99(1H, d, J=8.8), 8.80˜9.10(2H, br),10.96 (1H, s), 11.18(1H, s) Intermed. 124 (CDC13): 1.39(3H, t, J=7.1),1.66 (3H, s), 3.76(2H, m), 4.05(2H, m), 4.38(2H, q, J=7.1), 7.56 (2H, d,J=8.5), 8.03(2H, d, J=8.5) Intermed. 125 (CDC13): 2.61(3H, s), 4.79(2H,s), 7.46(2H, d, J=8.0), 7.96(2H, d, J=8.2) Intermed. 126 (CDC13):2.14(3H, s), 2.61(3H, s), 5.17(2H, s), 7.45(2H.d, J=8.5) 7.96(2H, d,J=8.5), Intermed. 127 (CDC13): 2.20(3H, s), 2.68(3H, s), 5.57(2H, s),7.73(1H, d, J=8.2), 8.22(1H, dd, J=8.2, 1.6), 8.65(1H, d, J=1.6)Intermed. 128 (CDC13): 2.10(3H, s), 2.56(3H, s), 4.18(2H, br. s),5.12(2H, s), 7.27˜7.31(3H, m) Intermed. 129 (CDC13): 2.11(3H, s),2.62(3H, s), 3.12(3H, s), 5.18(2H, s), 7.52(1H, d, J=8.0), 7.74(1H, br.s), 7.79(1H, dd, J=8.0, 1.6), 8.08(1H, d, J=1.6) Intermed. 130 (CDC13):2.12(3H, s), 3.14(3H, s), 4.43(2H, s), 5.18(2H, s), 7.55(1H, d, J=8.0),7.80(1H, b s), 7.83(1H, dd, J=8.0, 1.7), 8.12 (1H, d, J=1.7) Intemed.131 (DMSO-d6): 2.05(3H, s), 2.96(3H, 500 s), 2.92˜3.00(2H, m), 3.28˜3.32(MH+) (2H, m), 4.08˜4.13(2H, m), 4.67(1H, br. s), 5.15(2H, s), 5.44(1H,m), 6.76(1H, dd, J=8.2, 1.9), 6.96(1H, d, J=1.9), 7.07˜7.13 (1H, m),7.24˜7.44(4H, m), 7.93˜8.00(3H, m) Example 84 (DMSO-d6; HC1): 3.02(3H,s), 3.25˜3.35 470 (2H.m), 3.43˜3.53(2H, (MH+) m), 4.36˜4.43(2H, m),4.62(2H, s), 5.03(1H, d, J=9.1), 6.26 (1H, bs), 6.84(1H, dd, J=8.5,2.2), 7.03(1H, d, J=1.9), 7.12 (1H, dd, J=7.1), 7.24˜7.35(2H, m),7.38(1H, s), 7.44(1H, d, J=8.0) 7.47(1H, d, J=8.0), 8.01 (1H, d, J=8.2),9.06(1H, s), 8.90˜9.25 (2H, br), 11.21(1H, s) Intermed. 132 (CDC13):2.61(3H, s), 3.06(3H, s), 7.66(1H, dd, J=8.5, 2.2), 7.71(1H, d, J=8.5),8.20(1H, d, J=2.2) Intermed. 133 (CDC13): 3.09(3H, s), 4.42(2H, s),7.68(1H, dd, J=8.4, 1.8), 7.75(1H, d, J=8.4), 8.21(1H, d, J=1.8) Example85 (DMSO-d6; HC1): 3.07(3H, s), 2.98˜3.16 520 (2H, m), 3.43˜3.55(2H,(M+2)+ H, m), 4.35˜4.44(2H, m), 5.0˜5.08 (1H, m), 6.38(1H, br. s), 6.84(1H, dd, J=8.5, 2.2), 7.03(1H, d, J=2.2), 7.12(1H, dd, J=8.1, 8.0),7.24(1H, dd, J=8.0, 1.9), 7.30(1H, dd, J=8.0, 8.0), 7.44 (1H, d, J=8.0),7.52(1H, d, J=1.9), 7.72(1H, d, J=8.0), 8.00 (2H, d, J=8.5),8.95˜9.08(1H, m), 9.10˜9.25(1H, m), 9.47(1H, s), 11.20(1H, s) Intermed.134 (CDC13): 2.64(3H, s), 7.80(1H, dd,=8.2, 2.2), 8.19(1H, d, J=8.2),8.36(1H, d, J=2.2) Intermed. 135 (CDC13): 2.54(3H, s), 4.25(2H, br. s),7.01(1H, dd, J=8.2, 1.9), 7.29(1H, d, J=1.9), 7.74(1H, d, J=8.2)Intermed. 136 (CDC13): 2.60(3H, s), 3.06(3H, s), 7.51(1H, dd, J=8.2,1.9), 7.96(1H, d, J=8.2), 8.16(1H, d, J=1.9) Intermed. 137 (CDC13):3.09(3H, s), 4.41(2H, s), 6.76(1H, br. s), 7.53(1H, dd, J=8.2, 2.2),8.00(1H, d, J=8.2), 8.18(1H, d, J=2.2) Example 86 (DMSO-d6; HC1):3.08(3H, s), 3.0˜3.1 566 (2H, m), 3.45˜3.54(2H, (MH+) m), 4.38˜4.47(2H,m), 4.98˜5.08 (1H, m), 6.37(1H, br. s), 6.84 (1H, dd, J=8.5, 2.2),7.03(1H, d, J=2.2), 7.06˜7.16(2H, m), 7.30(1H, dd, J=8.2, 8.2), 7.44(1H, d, J=8.2), 7.46(1H, d, J=2.2), 7.94(1H, d, J=8.2), 8.01(2H, d,J=8.5), 8.94˜9.06(1H, br), 9.10˜9.24(1H, br), 9.36(1H, s), 11.21(1H, s)Intermed. 138 (CDC13): 2.55(3H, s), 2.70(3H, s), 4.31(2H, s), 5.17(2H,s), 6.95(1H, s), 7.02(1H, d, J=8.5), 7.15˜7.21(2H, m), 7.23˜7.31 (2H,m), 7.33˜7.44(6H, m), 7.74 (1H, dd, J=8.5, 2.2), 8.14(1H, d, J=2.8)Intermed. 139 (CDC13): 2.72(3H, s), 4.33(2H, s), 4.37(2H, s), 5.18(2H,s), 6.98(1H, s), 7.04(1H, d, J=8.5), 7.16˜7.22(2H, m), 7.25˜7.32 (2H,m), 7.34˜7.43(6H, m), 7.77 (1H, dd, J=8.8, 1.9), 8.14(1H, d, J=2.2)Intermed. 140 (DMSO-d6): 2.51(3H, s), 2.69(2H, 651 m), 2.94(2H, m),4.07(2H, m), (MH+) 4.11(2H, s), 4.60(1H, m), 5.15 (2H, s), 6.74(1H, d,J=10.7), 6.94(1H, m), 7.03˜7.58(16H, m), 7.91˜8.00(3H, m), 11.08(1H, s)Example 87 (DMSO-d6; HC1): 2.57(3H, s), 3.00˜3.30 561 (2H, m), 3.47(2H,m), (MH+) 4.18(2H, s), 4.37(2H, m), 4.92 (1H, d, J=9.6), 6.14(1H, br.s), 6.82(1H, dd, J=8.5, 2.2), 6.91 (1H, d, J=8.2), 7.02˜7.12(3H, m),7.18˜7.21(2H, m), 7.25˜7.35 (4H, m), 7.41(1H, d, J=2.2) 7.43(1H, d,J=8.0), 7.97˜8.02 (2H, m) Intermed. 141 (CDC13): 1.09(6H, t, J=7.1),2.55 (3H, s), 3.30(4H, q, J=7.1), 5.17(2H, s), 6.91(1H, bs), 6.99 (1H,d, J=8.5), 7.36˜7.44(5H, m), 7.69(1H, dd, J=8.5, 2.2), 8.02(1H, d,J=2.2) Intermed. 142 (CDC13): 1.10(6H, t, J=7.4), 3.31 (4H, q, J=7.4),4.39(2H, s), 5.19(2H, s), 6.94(1H, bs), 7.02 (1H, d, J=8.8),7.36˜7.44(5H, m), 7.72(1H, dd, J=8.8), 8.03 (1H, d, J=2.2) Intermed. 143(DMSO-d6): 0.88(6H, t, J=7.1), 603 2.68(2H, d, J=5.8), 2.95(2H, (MH+)m), 3.07(4H, q, J=7.1), 4.09(2H, m), 4.58(1H, m), 5.13(2H, s), 6.76(1H,d, J=6.6), 6.92˜7.14 (4H, m), 7.24˜7.44(7H, m), 7.54 (2H, d, J=6.9),7.90˜8.02(2H, m) Example 88 (DMSO-d6; HC1): 0.95(6H, t, J=7.1), 5133.13(4H, q, J=7.1), 2.95˜3.25 (MH+) (2H, m), 3.48(2H, m), 4.37 (2H, m),4.88(1H, d, J=10.2), 6.11(1H, br. s), 6.80˜6.88(2H, m), 6.95˜7.04(2H,m), 7.12(1H, dd, J=8.0, 0.8), 7.27˜7.34(2H, m), 7.44(1H, d, J=8.0), 8.01(2H, d, J=8.5), 8.54(1H, s), 8.6˜9.1 (2H, br), 9.85(1H, s), 11.19 (1H,s) Intermed. 144 (CDC13): 2.75(6H, s), 4.41(2H, s), 5.29(2H, s),7.15(1H, d, J=8.8), 7.35˜7.45(3H, m), 7.47˜7.52 (2H, m), 8.17(1H, dd,J=8.8, 2.2), 8.54(1H, d, J=2.2) Intermed. 145 (CDC13): 0.52˜0.62(6H, m),0.85˜0.94 (9H, m), 2.71(6H, s), 3.26˜3.35 (2H, m), 4.76(1H, t, J=6.2),5.19(2H, s), 7.05(1H, d, J=8.5), 7.32˜7.44(3H, m), 7.46˜7.55 (3H, m),7.90(1H, d, J=2.2) Intermed. 146 (CDC13): 0.48˜0.58(6H, m), 0.87 (9H, t,J=7.8), 2.71(6H, s), 2.74˜2.82(1H, m), 2.85˜2.91(1H, m), 3.04(2H, m),4.13(2H, m), 4.8˜4.86(1H, m), 5.16(2H, s), 6.82(1H, dd, J=8.5, 2.2),6.88 (1H, d, J=2.2), 7.01(1H, d, J=8.5), 7.20(1H, m), 7.29˜7.42 (6H, m),7.45˜7.52(2H, m), 7.91 (1H, d, J=8.5), 7.96˜7.98(2H, m), 8.20(1H, br. s)Intermed. 147 (DMSO-d6): 2.62(2H, m), 2.71˜2.75 560 (2H, m), 2.95(2H,m), 4.08 (MH+) (2H, m), 4.65˜4.72(1H, m), 5.24 (2H, s), 5.46(1H, br. s),6.75 (1H, dd, J=8.5, 2.2), 6.95(1H, d, J=2.2), 7.10(1H, dd, J=7.7, 7.7),7.24˜7.44(6H, m), 7.48˜7.54 (2H, m), 7.57(1H, dd, J=8.5, 2.2), 7.78(1H,d, J=2.2), 7.95 (1H, d, J=8.5), 7.98(1H, d, J=8.2), 11.10(1H, s) Example89 (DMSO-d6; HC1): 2.71(6H, s), 2.76˜2.82 470 (2H, m), 3.02(2H, m),(MH+) 4.13(2H, m), 4.64˜4.70(1H, m), 6.76(1H, dd, J=8.5, 2.2), 6.96 (1H,d, J=2.2), 7.01(1H, d, J=8.2), 7.10(1H, dd, J=8.0, 8.0), 7.28(1H, dd,J=8.0, 8.0), 7.38˜7.45 (2H, m), 7.65(1H, d, J=2.2), 7.96(1H, d, J=8.5),7.98(1H, d, J=8.0), 8.28(1H, br. s), 11.15(1H, s) Intermed. 148 (CDC13):2.70(1H, d, J=8.5), 2.81 560 (1H, d, J=8.5), 2.90(3H, s), (MH+) 3.04(2H,m), 3.25(3H, s), 4.12 (2H, t, J=4.7), 4.32(1H, dd, J=8.5, 4.7), 5.07(2H,s), 6.82(1H, dd, J=8.5, 2.2), 6.88(1H, s), 6.96(1H, d, J=8.2), 7.09(1H,dd, J=8.5, 1.7), 7.19(1H, dd, J=8.8, 1.4), 7.29˜7.45(7H, m), 7.51(1H, d,J=1.9), 7.90(1H, d, J=8.5), 7.96(1H, d, J=7.7), 8.29(1H, m) Example 90(DMSO-d6; HC1): 2.96(3H, s), 3.19 470 (3H, s), 3.23(2H, d, J=6.6), (MH+)3.46(2H, m), 4.37(2H, m), 4.54 (1H, t, J=6.6), 6.84(1H, dd, J=8.5, 1.9),6.96(1H, d, J=8.5), 7.01˜7.08(2H, m), 7.12(1H, dd, J=7.4, 7.4), 7.23(1H,m), 7.30 (1H, m), 7.44(1H, d, J=8.0), 8.01(2H, d, J=8.2), 8.85(1H, s),8.96(1H, br. s), 10.15(1H, s), 11.19(1H, s) Example 91 (DMSO-d6; HC1):2.96(3H, s), 3.18 487 (3H, s), 3.18(1H, m), 3.31(1H, (MH+) m), 3.40(2H,m), 4.38(2H, m), 4.48(1H, m), 6.95(1H, d, J=8.0), 7.05(1H, m), 7.16(1H,dd, J=8.5, 2.2), 7.22(1H, d, J=2.2), 7.46(2H, m), 7.68(1H, d, J=2.2),7.98(1H, m), 8.27(2H, m), 8.82(1H, br. s), 10.12(1H, br. s) Example 92(DMSO-d6; 2HC1): 2.94(3H, s), 469 3.17(3H, s), 3.22(2H, m), 3.46 (MH+)(2H, m), 4.38(2H, m), 4.51(1H, m), 6.81˜6.90(2H, m), 7.03(2H, dd, J=6.3,2.2), 7.12(2H, dd, J=7.4, 7.4), 7.27˜7.33(1H, m), 7.44(1H, d, J=8.0),8.01(2H, d, J=8.5), 8.8˜9.2(3H, br), 11.20 (1H, s)

[0873] TABLE 2 Compound * Intrinsic activity (%) ED₅₀ (nM) Isoproterenol100 140 BRL37344 29 104 CL316, 243 9 1700 Example 1 80 340 Example 2 1200.18 Example 4 80 0.52 Example 5 114 66 Example 6 119 33 Example 7 95 18Example 8 47 720 Example 9 85 750 Example 10 47 150 Example 11 95 26Example 12 113 0.14 Example 13 110 2.7 Example 14 97 2.8 Example 15 88110 Example 16 99 30 Example 17 53 910 Example 18 90 32 Example 25 952.1 Example 28 97 1000 Example 29 120 250 Example 30 110 1700 Example 31100 2200 Example 32 98 1600 Example 34 37 4600 Example 35 90 520 Example38 76 0.006 Example 40 97 200 Example 41 63 600 Example 43 104 85Example 45 89 17 Example 47 86 2000 Example 48 73 220 Example 50 85 0.94Example 52 78 2.6 Example 54 109 8.4 Example 55 76 230 Example 56 97 630Example 57 68 230 Example 58 91 550 Example 62 106 210 Example 66 106 72Example 67 109 28 Example 68 92 38 Example 69 94 0.016 Example 70 76 300Example 71 97 180 Example 72 80 0.00003 Example 73 102 0.038 Example 74114 0.74 Example 75 105 88 Example 76 131 520 Example 77 100 21 Example78 110 51 Example 79 107 1.2 Example 80 110 57 Example 81 98 6.2 Example82 130 2800 Example 83 79 740 Example 84 71 58 Example 85 70 56 Example87 138 84 Example 88 86 390 Example 89 73 350 Example 90 102 190 Example92 81 280

[0874] TABLE 3 Compound * Intrinsic activity (%) ED₅₀ (nM) Isoproterenol100 1.7 Example 2 82 56 Example 4 88 0.7 Example 7 90 1200 Example 9 106250 Example 25 70 510 Example 31 103 7700 Example 32 94 290 Example 38103 2.6 Example 40 92 13 Example 41 109 240 Example 43 77 4 Example 50112 0.19 Example 52 100 0.38 Example 54 118 25 Example 67 94 54 Example69 107 0.65 Example 71 88 110 Example 72 96 0.54 Example 92 126 1900

What is claimed is:
 1. A compound represented by the general formula (I)or a salt thereof:

in which R represents hydrogen atom or methyl, R¹ stands for hydrogenatom, halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R²stands for hydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro,wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl or CONHR⁶, with R⁵being lower alkyl, benzyl or NR⁴R^(4′) and R⁶ being hydrogen atom orlower alkyl, and R⁴ and R^(4′) may be identical with or different fromeach other and stand each for hydrogen atom, lower alkyl or benzyl, R⁶represents hydrogen atom or lower alkyl, X is methylene, both R⁷ and R⁸are hydrogen atom and R⁹ stands for hydrogen atom, amino, acetyl aminoor hydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 2. A compound represented by the general formula (I) or a saltthereof as claimed in claim 1:

in which R represents hydrogen atom, R¹ stands for hydrogen atom,halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R² stands forhydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro, wherein R³ ishydrogen atom, methyl, SO₂R⁵, formyl or CONHR⁶, with R⁵ being loweralkyl, benzyl or NR⁴, R⁴ and R^(6′) being hydrogen atom or lower alkyl,and R⁴ and R^(4′) may be identical with or different from each other andstand each for hydrogen atom, lower alkyl or benzyl, R⁶ representshydrogen atom or lower alkyl, X is methylene, both R⁷ and R⁸ arehydrogen atom and R⁹ stands for hydrogen atom, amino, acetylamino orhydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 3. A compound represented by the general formula (I) or a saltthereof as claimed in claim 2:

in which R represents hydrogen atom, R¹ stands for hydrogen atom,fluorine atom, chlorine atom, hydroxy or benzyloxy, R² stands forhydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R^(4′) or nitro, wherein R³ ishydrogen atom, methyl, SO₂R⁵, formyl or CONHR^(6′) and either one of R⁴and R^(4′) is hydrogen atom and the other one is hydrogen atom, loweralkyl or benzyl, with R⁵ being lower alkyl, benzyl or dimethylamino andR^(6′) being hydrogen atom or lower alkyl, R⁶ represents hydrogen atomor lower alkyl, X is methylene, both R⁷ and R⁸ are hydrogen atom, amino,acetylamino or hydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 4. A compound represented by the general formula (I) or a saltthereof as claimed in claim 2:

in which R represents hydrogen atom, R¹ stands for hydrogen atom,halogen atom, hydroxy or benzyloxy, R² stands for hydroxymethyl, NHR³,SO₂NR⁴R⁴ or nitro, wherein R³ is hydrogen atom, methyl, SO₂R⁵, formyl orCONHR^(6′) and R⁴ and R⁴ may be identical with or different from eachother and stand each for hydrogen atom, lower alkyl or benzyl, with R⁵being lower alkyl, benzyl or NR⁴R^(4′) and R^(6′) being hydrogen atom orlower alkyl, R⁶ represents hydrogen atom or lower alkyl, X is methylene,both R⁷ and R⁸ are hydrogen atom and R⁹ stands for hydrogen atom, amino,acetylamino or hydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 5. A compound or a salt thereof as claimed in claim 2, whereinthe general formula (I), both R and R¹ represent hydrogen atom, R²stands for hydroxymethyl, NHR³ or SO₂NR⁴R^(4′), wherein R³ is hydrogenatom, methyl, SO₂R⁵, formyl or CONHR⁶ and R⁴ and R⁴ may be identicalwith or different from each other and stand each for hydrogen atom,lower alkyl or benzyl, with R⁵ being lower alkyl, benzyl or NR⁴R^(4′).6. A compound or a salt thereof as claimed in claim 2, wherein, in theformula (I), R denotes hydrogen atom, R¹ stands for halogen atom orhydroxy, R² stands for NHSO₂R⁵ or SO₂NR⁴R^(4′), wherein R⁵ is loweralkyl, benzyl or NR⁴R⁴ and R⁴ and R^(4′) may be identical with ordifferent from each other and stand for hydrogen atom, lower alkyl orbenzyl.
 7. A compound represented by the general formula (I) or a saltthereof as claimed in claim 2:

wherein R represents hydrogen atom, R¹ stands for hydrogen atom, halogenatom-or hydroxy, R² stands for hydrogen atom, R⁶ represents hydrogenatom or lower alkyl, X is methylene, both R⁷ and R⁸ are hydrogen atom,amino, acetylamino or hydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 8. A compound represented by the general formula (I) or a saltthereof as claimed in claim 1:

wherein R represents methyl, R¹ stands for hydrogen atom, halogen atom,hydroxy, amino or hydroxymethyl, R² stands for NHR³ or SO₂NR⁴R⁴, whereinR³ represents SO₂R⁵, with R⁵ being lower alkyl, benzyl or NR⁴R^(4′), andR⁴ and R⁴ may be identical with or different from each other and standeach for hydrogen atom, lower alkyl or benzyl, R⁶ represents hydrogenatom or lower alkyl, X is methylene, both R⁷ and R⁸ are hydrogen atomand R⁹ stands for hydrogen atom, amino, acetylamino or hydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 9. A pharmaceutical composition comprising as an effectivecomponent, a compound or a salt thereof as claimed in claim 1, in aphysiologically or pharmacologically acceptable carrier.
 10. Amedicament as claimed in claim 1, wherein it is a drug compositioncomprising, as an effective component, a compound or a salt thereof asclaimed in claim 1 and a carrier medicamentally acceptable for theeffective component.
 11. A pharmaceutical composition as claimed inclaim 9, in the form of a drug suitable for therapeutic treatment orpreventive treatment of one of diabetes, obesity and hyperlipemia.
 12. Amethod for producing a compound represented by the general formula (I):

in which R represents hydrogen atom, R¹ stands for hydrogen atom,halogen atom, hydroxy, benzyloxy, amino or hydroxymethyl, R² stands forhydrogen atom, hydroxymethyl, NHR³, SO₂NR⁴R⁴ or nitro, wherein R³ ishydrogen atom, methyl, SO₂R⁵, formyl or CONHR⁶, with R⁵ being loweralkyl, benzyl or NR⁴R^(4′) and R⁶ being hydrogen atom or lower alkyl,and R⁴ and R^(4′) may be identical with or different from each other andstand each for hydrogen atom, lower alkyl or benzyl, R⁶ representshydrogen atom or lower alkyl, X is methylene, both R⁷ and R⁸ arehydrogen atom and R⁹ stands for hydrogen atom, amino, acetylamino orhydroxy, and

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl, comprising the step of reacting a compound represented by thegeneral formula (II):

in which R^(6′) represents hydrogen atom, halogen atom, a protectedhydroxyl group protected by a protecting group A, a protected aminogroup protected by acetyl group or a protected hydroxymethyl groupprotected by acetyl group, R^(2′) stands for hydrogen atom, for aprotected hydroxymethyl group in which the hydroxyl group is protectedby a protecting group A′″, for NHR³, for SO₂NR¹R⁴ or for nitro, whereinR^(3′) represents a protecting group for the amino group, methyl, SO₂R⁵,formyl or CONHR^(6′), with R⁵ being lower alkyl, benzyl or NR⁴R^(4′) andR^(6′) being hydrogen atom or lower alkyl, R⁴ and R^(4′) may beidentical with or different from each other and stand each for hydrogenatom, lower alkyl or benzyl, R⁶ denotes hydrogen atom or lower alkyl, A′represents a protecting group for the hydroxyl group, B is bromine atomor iodine atom and

1 indicates an asymmetric carbon atom with a compound represented by thegeneral formula (III):

in which Y represents hydrogen atom, R⁶ is hydrogen atom or lower alkyl,X is methylene, both R^(7′) and R^(8′) are hydrogen atom and R^(9′)stands for hydrogen atom, acetylamino or a protected hydroxyl groupprotected by a protecting group A″, and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl, wherein the protecting groups A, A′, A″, and A′″ as well as theprotecting group for the amino group in R^(3′) and the protecting acetylgroup in R^(1′) are eliminated for protection with the proviso that theprotecting group A is not eliminated if A is benzyl and R¹ is benzyloxy.13. A compound represented by the general formula (II):

in which R^(6′) represents hydrogen atom, halogen atom, a protectedhydroxy group protected by a protecting group A, a protected amino groupprotected by acetyl group or a protected hydroxymethyl group protectedby acetyl group, R^(2′) stands for SO₂NR⁴R^(4′) or nitro, A′ representsa protecting group for the hydroxy group, R⁴ and R^(4′) may be identicalwith or different from each other and stand for hydrogen atom, loweralky or benzyl, B is bromine atom or iodine atom and

1 indicates an asymmetric carbon atom with an absolute configuration of(R).
 14. A compound represented by the general formula (III):

in which Y represents hydrogen atom or a protecting group for the aminogroup, R⁶ is hydrogen atom or lower alkyl, X is methylene, both R^(7′)and R^(8′) are hydrogen atom and R⁹ stands for hydrogen atom,acetylamino or a protected hydroxyl group protected by a protectinggroup A″, and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 15. A compound represented by the general formula (IV):

in which R¹ represents hydrogen atom, halogen atom, a protected hydroxylgroup protected by a protecting group A, a protected amino groupprotected by acetyl group or a protected hydroxymethyl group in whichthe hydroxyl group is protected by acetyl group, R⁶ stands for hydrogenatom or lower alkyl, Y′ is hydrogen atom or a protecting group for theamino group, X is methylene, both R^(7′) and R^(8′) are hydrogen atomand R^(9′) is hydrogen atom, acetylamino or a protected hydroxyl groupprotected by a protecting group A″, A′ represents a protecting group forthe hydroxyl group,

1 indicates an asymmetric carbon atom and

2 indicates that the carbon atom is asymmetric provided that R⁶ is loweralkyl.
 16. A compound or a salt thereof as claimed in claim 2, whereinthe compound is selected from the group consisting ofN-[5-[2-[2-(7-acetylaminofluoren-2-yloxy)-ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;N-[3-[2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;N-[3-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]phenyl]methanesulfonamide;N-[5-[2-[2-(7-aminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]methanesulfonamide;N′[5-[-2-[2-(7-acetylaminofluoren-2-yloxy)ethylamino]-1-hydroxyethyl]-2-hydroxyphenyl]-N,N-dimethylsulfamide.17. A process for producing a compound represented by the generalformula (II):

Wherein R^(1′) represents a hydrogen atom, a halogen atom, a hydroxylgroup protected by a protecting group A, an amino group protected by anacetyl group, or a hydroxymethyl group protected by an acetyl group,R^(2′) represents SO₂NR⁴R^(4′) or a nitro group where R⁴ and R^(4′),which may be identical or different, are independently a hydrogen atom,a lower alkyl group or a benzyl group, A′ represents a protecting groupfor hydroxyl group, B represents a bromine atom or an iodine atom,

1 indicates an asymmetric carbon atom with an absolute configures of(R), said method comprising the following steps: (1) subjecting acompound represented by the general formula (V):

 wherein R¹, R², R⁴ and R⁴ each are as defined above, to asymmetricreduction; (2) optionally substituting an iodine atom for the bromineatom; and (3) protecting the hydroxyl group formed in step (1) to formthe compound of the formula (II).
 18. A process for producing a compoundrepresented by the general formula (III′) or (III″):

wherein Y represents a protecting group for amine, RE represents ahydrogen atom or a lower alkyl group, and

2 indicates an asymmetric atom when R⁶ is a lower alkyl group, Xrepresents a secondary nitrogen atom, an oxygen atom, a sulfur atom, ora methylene group, and when X is a secondary nitrogen atom, oxygen atomor sulfur atom, then R^(9′) is a hydrogen atom and one of R^(7′) andR^(8′) is a hydrogen atom and the other represents a hydrogen atom, anacetylamino group, or a hydroxyl group protected by a protecting groupA″, or when X is a methylene group, then R^(7′) and R^(8′) each are ahydrogen atom, and R^(9′) represents a hydrogen atom, an acetylaminogroup, or a hydroxyl group protected by a protecting group A″, saidmethod comprising the following steps of: (1) reacting a compoundrepresented by the general formula (VII):

 wherein Y, RE and

2 each are as defined above, with a compound represented by the generalformula (VIII):

 wherein X, R⁷, R^(8′) and R^(9′) each are as defined above, to producethe compound of the formula (III′); and (2) optionally deprotecting theprotecting group for amine to form the compound of the formula (III′).19. A process for producing a compound represented by the generalformula (IV′) or (IV):

wherein R^(1′) represents a hydrogen atom, a halogen atom, a hydroxylgroup protected by a protecting group A, an amino group protected by anacetyl group, or a hydroxymethyl group protected by an acetyl group, R⁶represents a hydrogen atom or a lower alkyl group, Y represents ahydrogen atom, A′ represents a protecting group for hydroxyl group,

1 indicates an asymmetric carbon atom,

2 indicates an asymmetric carbon atom when R⁶ is a lower alkyl group, Xrepresents a secondary nitrogen atom, an oxygen atom, a sulfur atom, ora methylene group, and when X is a secondary nitrogen atom, oxygen atomor sulfur atom, then R^(9′) is a hydrogen atom and one of R^(7′) andR^(8′) is a hydrogen atom and the other represents a hydrogen atom, anacetylamino group or a hydroxyl group protected by a protecting groupA″, or when X is a methylene group, then R^(7′) and R^(8′) each are ahydrogen atom, and R⁹ represents a hydrogen atom, an acetylamino group,or a hydroxyl group protected by a protecting group A″; or

wherein Y′ represents a protecting group for amine, and R¹, A′, R⁶, X,R^(7′), R^(8′), R^(9′),

1 and

2 each are as defined above, said method comprising the following stepsof: (1) reacting a compound represented by the general formula (II):

 wherein R¹, A′ and

1 each are defined as above, R^(2′) represents a nitro group, and Brepresents a bromine atom or iodine atom, with a compound represented bythe general formula (III):

 wherein Y, R⁶, X, R^(7′), R^(8′), R^(9′) and

2 each are defined as above, to form the compound of the formula (IV′);and (2) optionally converting Y into a protecting group Y′ for amine toform the compound of the formula (IV).
 20. Either of the optical isomersof a compound represented by the general formula (XII)

wherein R^(1′) is a halogen atom or a hydroxyl group protected by aprotecting group A, R is a nitro group, and

1 represents an asymmetric carbon atom.